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Medicinal plants utilized in the management of epilepsy in Ethiopia: ethnobotany, pharmacology and phytochemistry

November 2022
Chinese Medicine 17(1)

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CC BY 4.0

Authors:

Debre Markos University

Epilepsy is a common central nervous system (CNS) disorder that affects 50 million people worldwide. Patients with status epilepticus (SE) suffer from devastating comorbidities and a high incidence of mortalities. Antiepileptic drugs (AEDs) are the mainstream treatment options for the symptomatic relief of epilepsy. The incidence of refractory epilepsy and the dose-dependent neurotoxicity of AEDs such as fatigue, cognitive impairment, dizziness, attention-deficit behavior, and other side effects are the major bottlenecks in epilepsy treatment. In low- and middle-income countries (LMICs), epilepsy patients failed to adhere to the AEDs regimens and consider other options such as complementary and alternative medicines (CAMs) to relieve pain due to status epilepticus (SE). Plant-based CAMs are widely employed for the treatment of epilepsy across the globe including Ethiopia. The current review documented around 96 plant species (PS) that are often used for the treatment of epilepsy in Ethiopia. It also described the in vivo anticonvulsant activities and toxicity profiles of the antiepileptic medicinal plants (MPs). Moreover, the phytochemical constituents of MPs with profound anticonvulsant effects were also assessed. The result reiterated that a lot has to be done to show the association between herbal-based epilepsy treatment and in vivo pharmacological activities of MPs regarding their mechanism of action (MOA), toxicity profiles, and bioactive constituents so that they can advance into the clinics and serve as a treatment option for epilepsy.

Location map of Ethiopia. The different colored areas represent the regional states in Ethiopia where the use of plant-based medicines are reported

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Bioactive compounds isolated from plants with anticonvulsant/antiepileptic and convulsive activities

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Ethnobotanical data of MPs used to treat epilepsy and related symptoms in Ethiopia

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continued)

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Plant crude extracts with in vivo antiepileptic/anticonvulsant activities No. Scientific name PU Extract Seizure-inducing stimuli Animal models Doses (mg/kg) Treatment outcomes Refs.

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Birhan Chinese Medicine (2022) 17:129

https://doi.org/10.1186/s13020-022-00686-5

REVIEW

Medicinal plants utilized inthemanagement

ofepilepsy inEthiopia: ethnobotany,

pharmacology andphytochemistry

Yihenew Simegniew Birhan*

Abstract

Epilepsy is a common central nervous system (CNS) disorder that aﬀects 50 million people worldwide. Patients with

status epilepticus (SE) suﬀer from devastating comorbidities and a high incidence of mortalities. Antiepileptic drugs

(AEDs) are the mainstream treatment options for the symptomatic relief of epilepsy. The incidence of refractory

epilepsy and the dose-dependent neurotoxicity of AEDs such as fatigue, cognitive impairment, dizziness, attention-

deﬁcit behavior, and other side eﬀects are the major bottlenecks in epilepsy treatment. In low- and middle-income

countries (LMICs), epilepsy patients failed to adhere to the AEDs regimens and consider other options such as

complementary and alternative medicines (CAMs) to relieve pain due to status epilepticus (SE). Plant-based CAMs are

widely employed for the treatment of epilepsy across the globe including Ethiopia. The current review documented

around 96 plant species (PS) that are often used for the treatment of epilepsy in Ethiopia. It also described the in vivo

anticonvulsant activities and toxicity proﬁles of the antiepileptic medicinal plants (MPs). Moreover, the phytochemical

constituents of MPs with profound anticonvulsant eﬀects were also assessed. The result reiterated that a lot has to be

done to show the association between herbal-based epilepsy treatment and in vivo pharmacological activities of MPs

regarding their mechanism of action (MOA), toxicity proﬁles, and bioactive constituents so that they can advance into

the clinics and serve as a treatment option for epilepsy.

Keywords: Epilepsy, Medicinal plants, Anticonvulsant activity, Antiepileptic activity, Ethiopia

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Introduction

Epilepsy is a common central nervous system (CNS)

disorder and the fourth-largest cause of disease burden

worldwide [1]. It is mainly characterized by recurrent,

unprovoked seizures, which may trigger anxiety, depres-

sion, cognitive decline, schizophrenia, autism that can

deteriorate the quality of life (QOL) and increase the

incidence of mortality in patients [2, 3]. An imbalance

instigated by inhibition of the excitatory γ-aminobutyric

acid (GABA)-mediated neurotransmission and activation

of inhibitory glutamatergic neurotransmission within

the brain including hippocampal, neocortical, cortico-

thalamic, and basal ganglia network is often implicated

in the pathogenesis of epileptic seizures (ES) [4]. Epilepsy

can emanate from a genetic predisposition of the brain to

generate seizures or may be caused by brain damage due

to tumor, injury, stroke, infection, etc. [5] that can elicit

a wide array of abnormalities resulting in seizure gen-

eration [6]. According to WHO 2019 factsheet, approxi-

mately 50 million people around the globe are suﬀering

from unpleasant symptoms and comorbidities resulting

from ES [7]. It is reported that almost 80% of epilepsy

cases are found in low—and middle-income countries

(LMICs) [4] due to lack of suﬃcient antiepileptic drugs

(AEDs), high cost if any AEDs available, and undesir-

able outcomes of the existing AEDs [8]. In the case of

Open Access

Chinese Medicine

*Correspondence: yihenews@gmail.com

Department of Chemistry, College of Natural and Computational Sciences,

Debre Markos University, P.O. Box 269, Debre Markos, Ethiopia

Page 2 of 37

Birhan Chinese Medicine (2022) 17:129

Ethiopia, epilepsy is one of the 20 leading causes of mor-

tality, and 5.2 out of 1000 people are prone to ES in their

lifetime [9, 10]. In general, epilepsy has substantial eco-

nomic implications, predominantly in Africa, as it trig-

gered a great burden on the underprivileged healthcare

system of poor nations [11] as well as on patients owing

to the epilepsy-bound poor QOL, stigma, and discrimi-

nation in patients and relatives [12] that could ominously

increase healthcare expenditure and diminish overall

productivity [10].

Modulating the activity of GABAergic, glutamatergic,

purinergic neurotransmissions, cholinergic pathways and

ATPases is a viable option for the treatment of epilepsy

[13]. Attempts have been made to exploit the aforemen-

tioned neurotransmission pathways and enzymes impli-

cated in epileptogenesis for the design of novel chemical

agents to ameliorate the neurological deﬁcits responsi-

ble for the progression of epilepsy. us far, more than

30 AEDs have been approved for clinical use [14]. How-

ever, the AEDs succeeded only in the symptomatic relief

of epilepsy in patients without signiﬁcantly correcting

the underlying biochemical aberrations involved in epi-

leptogenesis [15]. Currently, the treatment of epilepsy

has mainly relied on such AEDs which can make patients

free of seizures upon proper treatments regimens.

Although the existing AEDs are eﬀective in the suppres-

sion of seizures in the vast majority of epilepsy patients,

30% of them (15% of children and 34% adults) developed

resistance towards AEDs, consequently, nonresponsive

towards AEDs [16, 17]. Moreover, the dose-dependent

neurotoxicity of AEDs such as fatigue, cognitive impair-

ment, dizziness, attention-deﬁcit behavior, and other side

eﬀects are the major bottlenecks in epilepsy treatment

[8]. Patients with refractory ES are at increased risk of

mortality and morbidity. Adjuvant therapies and AEDs

along with ketogenic diet supplements are employed

for the treatment of refractory ES [17]. Patients with

untreated and/or refractory epilepsy are often desper-

ate to seek nonconventional treatments including but

not limited to complementary and alternative medicines

(CAMs) [18]. e unaﬀordable price of newer AEDs and

the wider treatment gaps have inspired researchers to

focus on plants in the search for safe and eﬀective drugs

for the treatment of ES.

Current trends inthetreatment ofepileptic seizures

AEDs are pretty eﬀective in the treatment of epilepsy if

patients properly comply with treatment regimens. How-

ever, they are overpriced and seldom possess devastat-

ing and inevitable side eﬀects resulting in poor patient

compliance [19]. Treatment compliance or adherence is

a major factor that can dictate the outcomes of AEDs in

controlling the incidence of seizure attacks [20]. ere is

ample evidence suggesting the presence of a huge treat-

ment gap among epilepsy patients in LMICs ranging

from 25 to 100% [21]. In Africa, epilepsy is associated

with fear, misunderstanding, witchcraft, discrimination

and social stigmatization of patients and their families

that can be considered as a driving force for the observed

huge treatment gaps due to failure in several interven-

tion mechanisms employed and persistent antiepileptic

medications non-adherences (AEMNAs) [22]. Epilep-

tic patients experiencing AEMNAs are more prone to

have suboptimal treatment outcomes, recurrent seizure

attacks, intermittent hospital admissions, increased

healthcare expenditure, lowered level of productivity, and

thereby deteriorated QOL [23]. For instance, in Ethiopia,

the prevalence of AEMNAs was found to be in the range

of 21.8–68%. Poor healthcare system and medical ser-

vices, lack of medication access, economic constraints,

antiepileptic medication side eﬀects, and poor seizure

control status are among the factors which signiﬁcantly

contributed to the high burden of AEMNAs in Ethiopia

[24]. Moreover, the association of epilepsy with spiritual

and predestined fate as well as the presence of diﬀer-

ent cultural and spiritual beliefs with potential impacts

to enforce people to prefer CAMs for the treatment of

“spiritual disease” such as epilepsy [25] have signiﬁcantly

contributed to the high incidence of AEMNAs in diﬀer-

ent parts of Ethiopia. Overall, AEMNAs resulted in treat-

ment failure which in turn triggered devastating social

consequences, life-threatening comorbidities, employ-

ment restriction, physical injuries, and increased mortal-

ity [23]. For instance, in sub-Saharan Africa, untreated ES

are the common causes of death with status epilepticus

(SE), drowning, falls, burns, and sudden death contrib-

uting to epilepsy-associated mortality [26]. A study con-

ducted on 119 patients in Ethiopia revealed that about

58% of epileptic patients who acquired generalized tonic–

clonic seizures (GTCS) at a baseline evaluation with a

frequency of ≤ 8 times, 23.3% of them died [27]. Another

study revealed that among 316 persons with epilepsy, 20

(6.3%) died within 2year period mostly due to SE and

burn [28]. Accordingly, improving the patient compliance

towards the existing AEDs through novel intervention

approaches and bringing CAMs, especially antiepileptic

herbal formulation, into modern pharmacy shelves is an

option in the long term to tackle seizure-related morbid-

ity and mortality.

Importance ofcomplementary andalternative medicine

inEthiopia

According to National Center for Complementary and

Alternative Medicines (NCAM), CAMs are deﬁned as

a traditional healthcare system comprised of biologi-

cal, spiritual, alternative, physical, and energy therapies

Page 3 of 37

Birhan Chinese Medicine (2022) 17:129

[18]. A biological form of CAM that depends on natural

products is commonly sought for the treatment of dif-

ferent diseases worldwide [29]. It uses medicinal herbs,

medicinal animals, dietary supplements, antioxidants,

minerals, vitamins, etc. alone or in combination to diag-

nose, prevent and treat diﬀerent ailments [30]. Tradi-

tional medicines (TMs) of plant origin have become an

integral part of the healthcare system of developed and

developing countries [31] where 60% of the population

entirely depend on them to relieve diﬀerent types of ail-

ments. Medicinal plants (MPs) have played a vital role

in the treatment of human and livestock ailments since

immemorial [32] partly due to the presence of bioactive

secondary metabolites. Africa is the home of massive

biodiversity rich in diﬀerent types of animals and PS.

e continent is likely to have approximately 45,000 PS

of which 5000 species have medicinal importance [33].

Ethiopia is among the most diverse country located in

East Africa containing approximately 6500–7000 PS (12%

of them are endemic) in its ﬂora [34]. It is also endowed

with several languages, diverse cultures, and beliefs

which are the driving force for the existence of traditional

medical system plurality in the country [35]. Ethiopians

have been using MPs and medicinal animals for the pre-

vention, diagnosis, and treatment of diﬀerent ailments

since immemorial [36–40]. e healthcare demand

of 80% of the people and 90% livestock in the country

largely hinged on diﬀerent PS [35]. Nearly 800 MPs are

constantly employed to treat around 300 physical and

mental diseases in the traditional healthcare system of

Ethiopia [41]. e economic implication of MPs is note-

worthy in Ethiopia. It is estimated that approximately

56,000 tons of wild MPs were collected per annum, which

can potentially inject two billion Birr into the economy

[42]. Such magnitude of MPs consumption is strongly

associated with the accessibility, economic aﬀordability,

and cultural acceptability of MPs in diﬀerent communi-

ties of Ethiopia [43].

Data sources andsearch strategy

e present review describes the ethnobotany of MPs

used to treat epilepsy and related symptoms in Ethio-

pia. It also focuses on the invivo experimental evidence

about the pharmacological eﬃcacy of MPs in attenuat-

ing seizures in diﬀerent animal models and on the type of

bioactive compounds with profound anticonvulsant out-

comes from the phytochemical investigation of MPs to

establish a solid foundation for future research to develop

plant-based antiepileptic agents. For this purpose, eth-

nobotanical data about the antiepileptic MPs found in

Ethiopia were searched and downloaded from online

research databases (PubMed, Medline, Web of Science,

Google Scholar, Science Direct, and other institutional

repositories) written in English using speciﬁc keywords

such as “medicinal plants”, “medicinal herbs”, “ethnobo-

tanical study”, “traditional medicine”, “traditional medi-

cation”, “plant remedies”, “herbal remedies”, “traditional

healers”, “indigenous knowledge”, “folk medicine”, “tradi-

tional healers” + “Ethiopia”. Plant use reports for epilepsy

and related symptoms were compiled and examined in

terms of the habit of the MPs, parts used, condition of

remedy preparation, route of administration, number

of use citation (by Districts), target groups, etc. Based

on the ethnobotanical information, a combination of

keywords such as “scientiﬁc name of MPs” + “convul-

sions”, “anticonvulsant”, “seizure”, “antiseizure”, “epilepsy”,

“antiepileptic”, “epileptic seizure”, “phytochemical inves-

tigation”, “active compounds”, “phytochemical screening”,

“phytoconstituents”, “secondary metabolites”, “toxicity

proﬁles”, etc. were used to search and collect relevant

data on MPs with invivo antiepileptic activities, toxicity

proﬁles and to identify the phytochemicals (with already

known anticonvulsant activities) present in the target

MPs. e invivo antiepileptic activities of MPs were ana-

lyzed based on the type of seizure-inducing agents, ani-

mal model, eﬀective doses, and observed outcomes.

Results anddiscussion

Ethnobotany ofmedicinal plants used forthetreatment

ofepilepsy

Plant distribution acrossfamilies andgeography

In this review, a total of 96 PS was found to have tradi-

tional healthcare prominence for the treatment of epi-

lepsy and related symptoms in Ethiopia (Table 1). Of

which 79 and 8 PS (Agrocharis melanantha, Artemisia

abyssinica, Crotalaria spinose, Cucurbita pepo, Erian-

themum dregei, Myrica salicifolia, Solanum incanum,

and Vigna membrancea) were used to suppress ES in

humans and animals, respectively. Arundinaria alpina,

Azadirachta indica, Croton macrostachyus, Echinops

Kebericho, Embelia schimperi, Nicotiana tabacum, Oci-

mum lamiifolium, Satureja abyssinica and Vernonia

amygdalina were used to treat both human and live-

stock epilepsy cases. e reported MPs were distributed

across 43 families and the highest occurrence belonged

to Asteraceae (9, 20.93%), Fabaceae (8, 18.6%), Euphorbi-

aceae (7, 16.27%), Solanaceae (5, 11.63%), Lamiaceae (4,

9.3%) and Rubiacea (4, 9.3%). Apocynaceae, Celastraceae,

and Rutaceae were represented by 3 (6.98%) PS each. In

addition, Apiaceae, Cucurbitaceae, Verbenaceae, Malva-

ceae, Myrsinaceae, Myrtaceae, Oleaceae, Polygonaceae

and Vitaceae families possessed 2 (4.65%) PS each. Other

26 families possessed a single PS eﬀective against epi-

lepsy in Ethiopia. Asteraceae, Fabaceae, Euphorbiaceae,

and Solanaceae are the dominant families commonly

found in the Ethiopian and Eritrean ﬂora [44]. us, the

Page 4 of 37

Birhan Chinese Medicine (2022) 17:129

Table 1 Ethnobotanical data of MPs used to treat epilepsy and related symptoms in Ethiopia

No. Scientic name Family GF PU CP ROA TGs Study areas Refs.

1Acacia seyal Delile Fabaceae T B D N Hu Amaro District, SNNPR [62]

2Acalypha fruticosa Forssk Euphorbiaceae Sh L F O Hu Yalo District, AfR [63]

3Acokanthera schimperi (A. DC.) Benth.

& Hook.f. ex Schweinf Apocynaceae Sh R F/D – Hu Enarso District, AR [64]

4Agrocharis melanantha Hochst Apiaceae H R F N Li Bale Mountain National Park, OR [65]

5Ajuga integrifolia, Buch.-Hamn Lamiaceae H L D O Hu Ghimbi District, Selale Mountain

Ridges, Jimma Zone, OR [53, 66, 67]

Ap F O Hu Borecha District, OR [68]

6Ampelocissus bombycina (Baker)

Planch Vitaceae Cl R F O Hu Hawassa Zuria District, SNNPR [59]

7Artemisia abyssinica Sch. Bip. Ex A.

Rich Asteraceae H R F N Li Bale Mountain National Park, OR [65]

8Artemisia afra Jacq. Ex Willd Asteraceae H L, R, SB F N Hu Bale Mountains National Park, OR [69]

9Arundinaria alpina K. Schum Poaceae T L, Bu F O Hu/Li Dawuro Zone, SNNPR [70]

10 Asparagus africanus Lam Asparagaceae Sh L, R, SB F/D N Hu Ankober & Enarj Enawga Districts, AR [71]

11 Asplenium aethiopicum (Kunth) mett Aspleniaceae H L, R F N Hu Ankober District, AR [71]

12 Azadirachta indica A. Juss Meliaceae T L F O Hu/Li Adwa District, TR [72]

13 Balanites aegyptica (L.) Del Balantiaceae T R – N Hu Chifra District, AfR [73]

14 Biophytum umbraculum Welw Oxalidaceae H R F O Hu Dawuro Zone, SNNPR [60]

15 Brachiaria brizontha (A. Rich.) Stapf Poaceae H R F O Hu Dawuro Zone, SNNPR [60]

16 Brucea antidysenterica J.F.Mill Simaroubaceae Sh L F D Hu Adwa District, TR [74]

17 Breonadia salicina (Vahl) Hepper &

Wood Rubiaceae T S F/D O Hu Berta Ethnic Group, BGR [75]

18 Buddleja polystachya Luganiaceae T L, R, B D O, N Hu Dawuro Zone, SNNPR [60, 76]

19 Calpurnia aurea (Ait.) Benth Fabaceae Sh R F/D O Hu Berta Ethnic Group, BGR [75]

20 Capparis tomentosa Lam Capparidaceae Cl R D N Hu Enarj Enawga District, AR; Asgede

Tsimbila District, TR [77, 78]

21 Carissa edulis (Forssk). Vahl Apocynaceae Sh R – – Hu Asgede Tsimbila District, TR [78]

22 Caucanthus auriculatus Forssk Malpighiaceae Cl L F O Hu Gurage, Mareqo, Qebena, & Silti,

SNNPR [79]

23 Caylusea abyssinica (Fresen.) Fisch. &

C.A.Mey Resedaceae H L, R F O Hu Hamar District, SNNPR [80]

24 Chenopodium ambrosioides L Chenopodiaceae H L F O, N Hu Dawuro Zone, SNNPR [70]

25 Cissus petiolata Hook. f Vitaceae Cl S – D Hu Tahtay Koraro, Medebay Zana &

Asgede Tsimbla, TR [81]

26 Celosia polystachia (Forssk.) C.C.

Towns Amaranthaceae H L F O Hu Yalo District, AfR [63]

27 Clerodendrum myricoides (Hochst.)

R.Br. Ex Vatke Verbenaceae Sh L F D Hu Bale Mountains National Park, OR;

Asgede Tsimbila District, TR [69, 78]

28 Clutia abyssinica Jaub Euphorbiaceae Sh L F D Hu Aseko District, OR [82]

29 Crotalaria spinosa Hochst. ex Benth Fabaceae H L F O Li Mana Angetu District, OR [83]

30 Croton macrostachyus Del Euphorbiaceae T SB F/D O Hu Mana Angetu District, OR [83]

L – – Hu Asgede Tsimbila District, TR [78]

L F/D O Li Mana Angetu District, OR [83]

31 Cucumis ﬁcifolius A. Rich Solanaceae H R, L F O Hu Asendabo District, OR [84]

32 Cucurbita pepo L Cucurbitaceae Cl L F O Li Mana Angetu District & Jimma Zone,

OR [67, 83]

33 Desmodium repandum (Vahl) DC Fabaceae H R F/D N Hu Ankober District, AR [71]

34 Dicrocephula integrifolia (L. f.) Kuntaze Asteraceae H L F N, D Hu Dawuro Zone, SNNPR [60, 76]

35 Dregea schimperi (Decne.) Bullock Apocynaceae Cl L F O Hu Gurage, Mareqo, Qebena & Silti,

SNNPR [79]

36 Echinops Kebericho Mesﬁn Asteraceae H R F N Hu Kembatta Tembaro Zone, SNNPR [85]

R D N Li Baso Liben & Debre Elias Districts, AR [86]

Page 5 of 37

Birhan Chinese Medicine (2022) 17:129

Table 1 (continued)

No. Scientic name Family GF PU CP ROA TGs Study areas Refs.

R, RB F O, N Hu/Li Dawuro Zone, SNNPR [70]

37 Embelia schimperi Vatke Myrsinaceae T Fr F O Hu Debark Woreda, AR [87]

R D O Li Baso Liben & Debre Elias Districts, AR [86]

38 Erianthemum dregei (Eckl and Zeyh.)

V. Tiegh Loranthaceae T L, S, R F/D O Li Mana Angetu District, OR [83]

39 Eucalyptus globulus Labull Myrtaceae T L, Se F/D O, N Hu Kembatta Tembaro Zone, SNNPR [85]

40 Euphorbia tirucalli L Euphorbiaceae Sh R F/D O Hu Amaro District, SNNPR [62]

41 Fagaropsis angolensis (Engl.) Milne-

Redh Rutaceae T Se, L F O Hu Kochere District, SNNPR [88]

42 Ficus vasta Forssk Moraceae T B D N, D Hu Dega Damot District, AR [52]

43 Galinirea coﬀeoides Rubiaceae Sh L, R F O Hu Dawuro Zone, SNNPR [60, 76]

44 Gloriosa superba L Colchicaceae Sh L F O Hu Harla & Dengego valleys, DDAC [89]

R F/D O Hu Mana Angetu District, OR [83]

45 Guizotia scabra (Vis) Chiov Compositae H R D O Hu Ada’a District, OR [90]

46 Hagenia abyssinica (Bruce) J.F. Gmel Rosaceae T Fl – – Hu Bale Rural Communities, OR [91]

47 Hypericum quartinianum A. Rich Hypericaceae Sh L D D Hu Around Fiche District, OR [92]

48 Indigofera articulata Gouan Fabaceae Sh L, R F O Hu Yalo District, AfR [63]

49 Indigofera coerulea Roxb Fabaceae Sh R F O Hu Jeldesa Cluster, DDAC [93]

50 Inula confertiﬂora A. Rich Asteraceae Sh L F N Hu Enarj Enawga District, AR [77]

51 Jatropha curcas L Euphorbiaceae Sh Se F O Hu Gurage, Mareqo, Qebena & Silti,

SNNPR [79]

52 Jasminum abyssinicum Hochst. Ex DC Oleaceae Cl L F N Hu Kembatta Tembaro Zone, SNNPR [85]

53 Justitia schimperiana Hochst. ex Nees Acanthaceae Sh L F O, D Hu Dawuro Zone, SNNPR [70]

54 Lagenarin abyssinica (Hoof. f) C.

Jeﬀrey Cucurbitaceae H L F N Hu Asendabo District, OR [84]

55 Laggera crispata (Vahl) Hepper &

Wood Asteraceae Sh R F O Hu Yilmana Densa & Quarit Districts, AR [42]

56 Lobelia gibberoa Hemsl Lobeliaceae T Se D O Hu Gubalafto District, AR [61]

57 Maytenus gracilipes (Welw.ex Oliv)

Exell Celastraceae Sh L D O Hu Bale Mountains National Park, OR [69]

58 Maytenus heterophylla (Eckl. & Zeyh.)

Robson Celastraceae Sh L F O Hu Gurage, Mareqo, Qebena & Silti,

SNNPR [79]

59 Maytenus senegalensis (Lam.) Excell Celastraceae Sh Se F/D O Hu Wonago District, SNNPR [45]

60 Myrica salicifolia Hochst. ex A. Rich Myrsinaceae T B D N Li Hulet Eju Enese District, AR [35]

61 Nicotiana tabacum L Solanaceae Sh R D O, N Hu Mana Angetu District, OR; Ankober

District, AR [71, 83]

L F D, N Hu Fadis & Dugda Districts, OR; Ankober

District, AR [71, 94, 95]

L F O Li Mana Angetu District, OR [83]

62 Ocimum canum Sims Lamiaceae H L F N Hu Dawuro Zone, SNNPR [70]

63 Ocimum lamiifolium Hochst,ex Benth Lamiaceae H L F O, N, D Hu/Li Dawuro Zone, SNNPR [70]

64 Olea europaea L Oleaceae T L D N Hu Hulet Eju Enese District, AR [35]

65 Olinia rochetiana A. Juss Oliniaceae T R F/D N Hu Ankober District, AR [71]

66 Opuntia ﬁcus-indica (L.) Miller Cactaceae H L F D Hu Debark District, AR [87]

67 Pavetta abyssinica Fresen Rubiaceae Sh Bu, Se F N Hu Kembatta Tembaro Zone, SNNPR [85]

68 Pentas schimperiana (A. Rich) Vatke Rubiaceae Sh RB F/D O Hu Wonago District, SNNPR [45]

69 Plectranthus edulis Vatke Lamiaceae H L, R - O Hu Abay Chomen District, OR [96]

70 Pterolobium stellatum Forsk. Brenan Fabaceae Sh R F/D N Hu Hulet Eju Enese District, AR [35]

Wh F O Hu Bahir Dar Zuria District, AR [97]

L, R F N Hu Hamar District, SNNPR [80]

71 Rhamnus staddo A. Rich Rhamnaceae Sh L F N Hu Enarj Enawga District, AR [77]

72 Rhus vulgaris Meikle Anacardiaceae Sh L F O, N, D Hu Dawuro Zone, SNNPR [70]

Page 6 of 37

Birhan Chinese Medicine (2022) 17:129

mere presence of such PS in a relatively higher number

in the antiepileptic MPs list is not a surprise. Overall,

the data showed the cultural signiﬁcance and medicinal

importance of Asteraceae, Fabaceae, Euphorbiaceae, and

Solanaceae families in the management of ES in Ethiopia.

e dominance of Asteraceae, Fabaceae, Euphorbiaceae,

and Solanaceae families were also reported in several

ethnobotanical surveys conducted to document the MPs

and associated indigenous knowledge used to treat diﬀer-

ent ailments in Ethiopia [45, 46].

TMs, especially MPs are routinely used for the man-

agement of diﬀerent diseases in the traditional health-

care system of the Regional States of Ethiopia [47–53].

Although these Regional States share some common

entities, they have distinct biodiversities, agro-ecology,

cultures, livelihood, values, beliefs, etc. which nurture the

indigenous knowledge and traditional practices of dwell-

ers. Hence, multifaceted treatment approaches and mis-

cellaneous traditional remedies are prevalent in diﬀerent

cultural groups of Ethiopia [36, 44, 54, 55]. In line with

this fact, the present literature review reiterated that the

use citations of antiepileptic MPs are widely distributed

across the diﬀerent regional states of Ethiopia (Fig.1):

Oromia (29 PS), Amhara (25 PS), Southern Nations,

Nationalities and Peoples (33 PS), Afar (4 PS), Tigray (8

PS), Benshangul-Gumuz (3 PS) and Dire Dawa Adminis-

tration Council (2 PS). More than 70% of MP species pre-

scribed for the treatment of seizure in Ethiopia belonged

to the three most populous and diverse regions, namely

Oromia, Amhara, and the SNNP Regional States. is

may be attributed to the presence of diﬀerent biodiversi-

ties, cultural pluralities, and thereby rich indigenous MPs

knowledge and practice in the regions. Despite the cross-

cultural connections and neighborhood manifested by

the long common border between Oromia and Amhara

regions as well as Oromia and SNNP regions, the consen-

sus of THs on antiepileptic MPs was quite low, only a few

MPs were commonly used across the regions.

Parts used, condition ofpreparation, andmode

ofadministration ofMPs

Among the reported 95 MPs, shrubs accounted for 35

(36.46%) PS. Herbs 30 (31.25%) and trees 21 (21.88%)

were the second and third most abundant growth forms

of MPs. On the other hand, 10 (10.42%) MPs were

climbers. e relative abundance of shrubs in Ethiopian

ﬂora and its accessibility in year-round may have con-

tributed to higher use citation of shrubs in antiepileptic

medication preparation [35]. e THs of Ethiopia pre-

ferred leaves, (66, 44. 59%) over other plant parts for

Table 1 (continued)

No. Scientic name Family GF PU CP ROA TGs Study areas Refs.

73 Rumex nepajensis Spreng Polygonaceae Sh R F N Hu Borecha District, OR [68]

74 Ruta chalepensis L Rutaceae Sh L, Se F N Hu Hulet Eju Enese District, AR [35]

75 Satureja abyssinica (Benth.) Briq Lamiaceae H L F N Hu/Li Dawro Zone, SNNPR [60, 76]

76 Securidaca longepedunculata Fres Polygonaceae T R D N Hu Enemay District, AR [39]

77 Solanum incanum L Solanaceae Sh R F O Li Mana Angetu District, OR [83]

78 Sida rhombifolia L Malvaceae H R – N Hu Tahtay Koraro, Medebay Zana &

Asgede Tsimbla, TR [81]

79 Sida schimperiana Hochst. Ex A.Rich Malvaceae Sh – F O Hu Wonago District, SNNPR [45]

80 Syzygium guineense (Willd.) DC Myrtaceae T S D O, N Hu Berta Ethnic Group, BGR [75]

81 Tragia cinerea (Pax) Gilbert and Radcl.-

Smith Euphorbiaceae Cl R D O Hu Menz Gera-Midir District, AR [98]

82 Tynura pseudochina L Compositae Sh L F O Hu Borecha District, OR [68]

83 Urera hypselodendron (Hochst.) ex

A. Rich Urticaceae Cl R D O Hu Hulet Eju Enese District, AR [35]

84 Vangueria volkensii K.Schum Rubiaceae Sh L, R F O Hu Hamar District, SNNPR [80]

85 Verbena bonariensis Verbenaceae H L D N Hu Mojana District, AR [99]

86 Vernonia amygdalina Del Asteraceae Sh L, B F O, D Hu/Li Dawuro Zone, SNNPR [70]

87 Vigna membrancea (L.) A. Rich Fabaceae Cl L, R F/D O Li Abay Chomen & Kersa Districts, OR [55, 96]

88 Withania somnifera (L.) Dun Solanaceae Sh R F/D O Hu Mana Angetu District, OR [83]

89 Xanthium stramonium L Solanaceae H L F D Hu Fadis District, OR [95]

90 Zingiber oﬃcinale Roscoe Zingiberaceae H R F O Hu Amaro District, SNNPR [62]

GF growth forms, T Tree, Sh shrub, H herb and Cl climber, Plant PU par ts used, L leaf (), S stem, SB stembark, R root, RB rootbark, Bd buds, Ap apex, Se seed, Wh whole

plant, Ar aerial part (), Bu bulbs, Lx latex, Fr fruit, Fl ower and Rh rhizome, CP condition of preparation, F fresh, and D dry, ROA routes of administration, O Oral, N nasal,

D dermal and Au auricular, TGs target groups, Hu Human and Li livestock, Reginal states of Ethiopia: AR amhara region, AfR Afar region, BGR Benshangul-Gumuz region,

DDAC dire dawa administration council, OR oromia region, TR tigray region, SNNPR southern nations, nationalities and peoples and peoples region

Page 7 of 37

Birhan Chinese Medicine (2022) 17:129

the preparation of remedies. ey also often used roots

(52, 34.14%) and seeds (10, 6.76%) for the formulation

of medicinal recipes. In addition, bulbs, stembark, root-

bark, apex, rhizome, ﬂowers, fruits, the whole plant,

and aerial part of MPs were also used for the extraction

of eﬀective medicines for seizure. e presence of bio-

active compounds, both in therapeutic abundance and

variety, in leaves and roots may be associated with the

curative eﬀects of such recipes against epilepsy [56, 57].

Fresh organs of plants (81, 64.8%) were often employed

for the preparation of antiepileptic medications in

Ethiopia. Dry forms of plant parts (23, 18.4%) were also

used for the preparation of remedies. Nearly 17% of

plant parts were used regardless of the condition they

exist (either fresh or dry). As fresh plant parts are rich

in bioactive metabolites, they are frequently sought for

the formulation of remedies not only for epilepsy but

also for other ailments in Ethiopia. In addition, fresh

plant parts are convenient to prepare medications using

crushing, squeezing, maceration, infusion, decoction,

etc., and can be ready for use in a short period as com-

pared to dry plant organs [44].

Diverse approaches and strict procedures are followed

by the THs for the preparation of remedies: abstraction

of pharmacologically relevant crude extract or essential

oils from diﬀerent plant organs in Ethiopia [47, 58, 59].

Depending on the perceived knowledge of the THs, some

may prefer crushing for remedy preparation while others

may use tying or burning of the same plant part for the

same ailment. e antiepileptic medications in Ethiopia

were most commonly prepared using crushing, squeez-

ing, maceration, pounding, grinding, decoction, etc. tech-

niques. Water was the main extraction solvent employed

in most preparations to tailor the concentration of the

recipe to the supposed level of therapeutic eﬃcacy and

to avoid dose-related toxicities in patients [45]. Additives

such as milk, “tella” (local beer), “teﬀ injera” (ﬂat bread),

sugar, etc. [60–62] were used to improve the taste of the

recipe and to enhance patient compliance towards the

formulations. Most of the antiepileptic herbal formu-

lations were administered through the oral route (63,

51.64%) by drinking, chewing, etc. followed by nasal (41,

33.61%) in the form of sniﬃng, smoking, and fumiga-

tion. Dermal route of administration (ROA) (18, 14.75%)

Fig. 1 Location map of Ethiopia. The diﬀerent colored areas represent the regional states in Ethiopia where the use of plant-based medicines are

reported

Page 8 of 37

Birhan Chinese Medicine (2022) 17:129

(through fumigation and washing) was seldom employed

for the delivery of antiseizure herbal medications in

the Ethiopian context. Oral is described as the primary

ROA in several ethnobotanical studies conducted else-

where [48, 59] due to the fast onset of action and ease of

application.

Multiple medicinal plants prescriptions forthetreatment

ofepilepsy

Combinations of two or more PS are seldom used to for-

mulate remedies for epilepsy and related symptoms in

Ethiopia and elsewhere [100]. is is based on the fact

that the consumption of multiple MPs could have poten-

tial synergistic outcomes and thereby enhanced pharma-

cological activities. For instance, the roots of four MPs

including Guizotia scabra, Ajuga integrifolia, Foeniculum

vulgare, and Withania somnifera have been used for the

preparation of remedy that can be taken through the oral

route in Adaꞌa District, Oromia Regional State, Ethiopia

[90] that can potentially attenuate convulsions in humans

(Table 2). On the other hand, leaves of Artemisia abys-

sinica, Brucea antidysentrica, and Cucumis ﬁcifolius

were employed for the preparation of recipes eﬀective

against epilepsy, when taken orally, around Jimma, Oro-

mia Regional State, Ethiopia [101]. Similarly, the leaves of

Nicotiana tabacum, Ocimum lamiifolium, and Withania

somnifera were also used for the preparation of remedies

that can be applied externally (dermal route) to relieve

seizure [102]. Herbalists living around Fiche District,

Oromia Regional State, Ethiopia prepare a remedy for

epilepsy from leaves of Hypericum quartinianum, Podo-

carpus falactus, and Teclea nobilis for external applica-

tion through the nasal ROA [92]. e diﬀerent classes of

phytochemicals such as alkaloids, ﬂavonoids, terpenoids,

etc. present in these MPs and their combined eﬀect in

enhancing the relative abundance/concentration and

amplifying the pharmacological eﬃcacy through syner-

gism may be associated with the preparation of eﬃcient

antiepileptic recipes from multiple MPs. Ocimum lamii-

folium, Nicotiana tabacum, Ruta chalepensis and Witha-

nia somnifera were most frequently sought MPs for the

preparation of antiseizure medications, each become

part of two diﬀerent formulations [35, 90, 94, 102]. e

wide application of Ocimum lamiifolium, Nicotiana

tabacum, Ruta chalepensis and Withania somnifera in

diﬀerent formulations might be due to the presence of

Table 2 Ethnobotanical data of multiple MPs prescriptions used to treat epilepsy and related symptoms in Ethiopia

GF growth forms, T Tree, Sh shrub, H herb, Cl climber, PU plant parts used, L leaf, R root, Se seed, Ar Aerial part, Bu bulbs and Fr fruit, CP condition of preparation, F Fresh

and D dry, ROA routes of administration, O Oral, N nasal and D dermal, Reginal states of Ethiopia AR amhara region, AfR afar region, BGR benshangul-gumuz region,

DDAC dire dawa administration council, OR Oromia region, TR Tigray region, SNNPR southern nations, nationalities and peoples and peoples region

No. Scientic name Family GF PU CP ROA Study area Refs.

1Artemisia abyssinica Sch. Bip. Ex A. Rich Asteraceae H L F O Jimma Area District, OR [101]

2Brucea antidysentrica J.F. Mill Simaroubaceae Sh L F

3Cucumis ﬁcifolius A. Rich Solanaceae Cl L F

1Embelia schimperi Vatke Myrsinaceae T Fr F O Debark District, AR [87]

2Guizotia abyssinica (L. f.) Cass Asteraceae H Se D

1Fagaropsis angolensis (Engl.) Milne-Redh Rutaceae T Se D O Kochere District, SNNPR [88]

2Solanum spp. Solanaceae H L F

1Guizotia scabra (Vis) Chiov Compositae H R D O Ada’a District, OR [90]

2Ajuga integrifolia, Buch.-Hamn Lamiaceae H R F/D

3Foeniculum vulgare Mill Apiaceae H R F/D

4Withania somnifera (L.) Dun Solanaceae Sh R F/D

1Hypericum quartinianum A. Rich Hypericaceae Sh L D D Around Fiche District, OR [92]

2Podocarpus falactus (Thunb.) R. B. ex Mirb – T L F

3Teclea nobilis Del Rutaceae T L F

1Nicotiana tabacum L Solanaceae H L F D Dugda District, OR [94]

2Ocimum lamiifolium Hochst Lamiaceae H L F

1Nicotiana tabacum L Solanaceae H L F D Seru District, OR [102]

2Ocimum lamiifolium Hochst Lamiaceae H L F

3Withania somnifera (L.) Dun Solanacae Sh L F

1Pterolobium stellatum Forsk. Brenan Fabaceae Cl R F N Hulet Eju Enese District, AR [35]

2Ruta chalepensis L Rutaceae Sh R F

1Ruta chalepensis L Rutaceae Sh L, Se F N Hulet Eju Enese District, AR [35]

2Allium sativum L Alliaceae H Bu F/D

Page 9 of 37

Birhan Chinese Medicine (2022) 17:129

convulsion-suppressive bioactive compounds in such

MPs. For obvious reasons, the use of formulations of

multiple MPs is a common practice in the treatment of

epilepsy in diﬀerent parts of the world [103].

Global importance ofthemedicinal plants inthetreatment

ofEpilepsy

Among the reported MPs for the treatment of epilepsy

and related symptoms in Ethiopia, 34 PS were also rou-

tinely used for the same indications in diﬀerent parts of

the world including Africa, Asia, the Middle East, and

Latin America (Table3). Among these, Carissa edulis

was the most popular (cited in six countries) antiepilep-

tic MP frequently used to control seizure in Ethiopia,

Nigeria, South Africa, Uganda, Malawi, and Kenya

[104–108]. Similarly, Maytenus senegalensis was another

well-known (cited in ﬁve countries) anticonvulsant MP

in Africa including Ethiopia, Uganda, Zimbabwe, South

Africa, and Guinea-Bissau [100, 106, 107, 109]. Witha-

nia somnifera was another multipurpose MP (cited in

four countries) used to control convulsions in Ethiopia,

Lesotho, India, and in East African countries [107, 110,

111]. Moreover, Acacia seyal, Acalypha fruticosa, Allium

sativum, Balanites aegyptica, Biophytum umbraculum,

Table 3 List of MPs plants used to treat epilepsy and related symptoms in other parts of the world

GF growth forms, T Tree, Sh shrub, H herb, Cl climber, PU plant parts used, L Leaf, S stem, SB stembark, R root, RB rootbark, Wh whole plant, Ar Aerial part, Bu bulbs, Lx

latex, Fr fruit, and Rh rhizome

No. Scientic name Family GF PU Country/region Refs.

1Acacia seyal Fabaceae T R Tanzania and Uganda [106, 112]

2Acalypha fruticosa Euphorbiaceae Sh L, R Tanzania and Kenya [113, 114]

3Allium sativum Alliaceae H Bu India and Cameron [103, 115]

4Artemisia afra Asteraceae H L South Africa [105]

5Arundinaria alpina Poaceae T R Uganda [138]

6Asparagus africanus Asparagaceae Sh R Cameron [127]

7Azadirachta indica Meliaceae T L India [128]

8Balanites aegyptica Balantiaceae T L, B, R Mali and Saudi Arabia [116, 117]

9Biophytum umbraculum Oxalidaceae H L, Wh Cameron and Uganda [115, 118]

10 Capparis tomentosa Capparidaceae Cl L Uganda [106]

11 Carissa edulis Apocynaceae Sh L,R, RB, Fr Nigeria, South Africa, Uganda, Malawi and Kenya [104–108]

12 Chenopodium ambrosioides Chenopodiaceae H L Democratic Republic of Congo [139]

13 Clerodendrum myricoides Verbenaceae Sh L, R South Africa and Kenya [100, 119]

14 Clutia abyssinica Euphorbiaceae Sh R Rwanda [129]

15 Croton macrostachyus Euphorbiaceae T B Cameron [140]

16 Cucurbita pepo Cucurbitaceae Cl – Nigeria [130]

17 Eucalyptus globulus Myrtaceae T L, B Kenya [131]

18 Euphorbia tirucalli Euphorbiaceae S Lx, Ar Somalia and East Africa [120, 121]

19 Indigofera arrecta Fabaceae Sh L, R South Africa and Nigeria [100, 122]

20 Indigofera articulata Fabaceae Sh Wh India [132]

21 Indigofera coerulea Fabaceae Sh L India [133]

22 Jatropha curcas Euphorbiaceae Sh L Nigeria [134]

23 Maytenus heterophylla Celastraceae Sh R East Africa [107]

24 Maytenus senegalensis Celastraceae Sh L, R, Uganda, Zimbabwe, South Africa and Guinea-Bissau [100, 106, 107, 109]

25 Myrica salicifolia Myrsinaceae T B Uganda [118]

26 Nicotiana tabacum Solanaceae H L Nigeria and Cameron [115, 123, 124]

27 Olea europaea Oleaceae T B, R, Fr Kenya [108]

28 Opuntia ﬁcus-indica Cactaceae H Fl India [135]

29 Ruta chalepensis Rutaceae Sh Ar Morocco and Mexico [125, 126]

30 Sida rhombifolia Malvaceae H Wh India [136]

31 Syzygium guineense Myrtaceae T SB West Africa [109]

32 Withania somnifera Solanacae H S, R Lesotho, East Africa and India [107, 110, 111]

33 Xanthium stramonium Solanaceae H Wh India [141]

34 Zingiber oﬃcinale Zingiberaceae H Rh Japan [137]

Page 10 of 37

Birhan Chinese Medicine (2022) 17:129

Clerodendrum myricoides, Euphorbia tirucalli, Indigofera

arrecta, Maytenus heterophylla, Nicotiana tabacum, and

Ruta chalepensis were the other MPs reported for their

usefulness against convulsions in at least three coun-

tries [100, 103, 106, 107, 112–126]. e remaining MPs:

Artemisia afra, Asparagus africanus, Azadirachta indica,

Capparis tomentosa, Clutia abyssinica, Croton macros-

tachyus, Cucurbita pepo, Eucalyptus globulus, Indigofera

articulata, Indigofera coerulea, Jatropha curcas, Myrica

salicifolia, Olea europaea, Opuntia ﬁcus-indica, Sida

rhombifolia, Xanthium stramonium, and Zingiber oﬃci-

nale were indicated for epilepsy in Ethiopia and at least

one other country [105, 106, 108, 109, 118, 127–137].

e extensive use of MPs across diﬀerent countries of

the globe echoed the existence of shared ethnopharma-

cological knowledge among the THs, the importance of

such MPs in the healthcare system of LMIC, especially in

tropical and southern Africa, and more importantly, the

pharmacological eﬃcacy of the MPs in the treatment of

epilepsy and related symptoms.

Pharmacological evidence ofreported medicinal

plants

Animal models forscreening ofanticonvulsant

orantiepileptic agents

e anticonvulsant or antiseizure activity of MPs

claimed by THs for the management of epilepsy could

be veriﬁed by using diﬀerent invitro and invivo experi-

ments. In 1937, electrically-induced convulsions in cats

were used to check the bioactivity of phenytoin, the

ﬁrst modern AED [142]. Later, this initiative paved the

way for the discovery of other seizure models respon-

sible for the discovery of more safe and eﬃcacious

second-generation AEDs such as lamotrigine, leveti-

racetam, topiramate, lacosamide, pregabalin, etc. [143].

e ability of crude extracts or bioactive compounds

to suppress diﬀerent forms of seizures can be exam-

ined by animal models by artiﬁcially induced convul-

sions using maximal electroshock (MES) or drugs such

as pentylenetetrazol (PTZ), picrotoxin (PIC), strych-

nine (STR), pilocarpine (PLC), isonicotinic hydrazide

acid (INH), Kainic acid (KA), 4-aminophylline (AMP),

bicuculline (BIC), etc. [144]. e similarity in the pat-

tern of seizure triggered by diﬀerent stimuli in animal

models with humans, simplicity upon execution, quick

response rate, and most importantly, predictive clini-

cal outcomes in humans [145] make the invivo seizure

models trustworthy in epilepsy research. In general,

MES acute seizure tests characterized by tonic exten-

sions of forelimbs in and hind limbs followed by all

limb clonus in mice/rat; subcutaneous PTZ acute sei-

zure tests manifested by myoclonic jerks followed

by unilateral forelimb and bilateral clonus, vibrissae

twitching in mice/rats and a Kindled rodent model of

chronic hyperexcitability characterized by unilateral

and bilateral forelimbs clonus that progresses to rearing

and falling in rats are the most common and “clinically

validated” models for early evaluation of AEDs [142].

Albeit, the aforementioned acute seizure models failed

to trace bioactive compounds eﬀective against refrac-

tory or drug-resistant seizures. us, there had been

a pressing need for the discovery of alternative seizure

models which can embrace the deviations observed in

“clinically validated” models. More recently, several

non-mammalian seizure models consisting of fruit

ﬂies (Drosophila melanogaster), medicinal leeches

(Hirudo verbena), planaria, roundworms (Caenorhab-

ditis elegans), tadpoles (Xenopus laevis), zebraﬁsh

(Danio rerio), etc. were recognized for their versatility

to assess the anticonvulsant activities of synthesized

compounds or plant extracts [146, 147]. Of which, the

zebraﬁsh larvae were the most frequently used seizure

model because of its high fertility rate and develop-

ment, similar CNS organization with mammals which

can be observed in translucent egg and embryo make

it ideal to study CNS disorders provoked by external

stimuli [148]. PTZ, KA, PLC and electrical stimulation

are employed to induce convulsions in in the aforesaid

non-mammalian seizure models [147].

In vivo pharmacological activities ofantiepileptic

medicinal plants

CAMs, especially herbal remedies are extensively used

for the treatment of epilepsy across the globe due to

their desirable treatment outcomes and tolerable side

eﬀects [144]. Moreover, herbal therapies may yield a

new horizon for treating patients seeking inexpen-

sive treatments for untreated epilepsy and experienc-

ing refractory seizures. Taking the popularity of the

MPs prescribed for treatment and management of epi-

lepsy in diﬀerent cultural groups across the globe into

account, preliminary invitro and/or invivo pharmaco-

logical evaluation of MPs and phytochemical isolation

of bioactive compounds have been conducted to test

the validity of the hypothesis made by THs found else-

where. Researchers employed diﬀerent animal models

to quantify the extent of suppression of diﬀerent forms

of seizures induced via MES, PTZ, PIC. STR, PLC,

NIH, and BIC by the crude extracts or solvent fractions

of MPs claimed to have potential anticonvulsant activi-

ties. is section highlighted the invivo anticonvulsant

activity of MPs (Table4) whereby ethnobotanical stud-

ies conducted in Ethiopia and other parts of the world

reiterated their profound pharmacological activities

against epilepsy and related symptoms.

Page 11 of 37

Birhan Chinese Medicine (2022) 17:129

Table 4 Plant crude extracts with in vivo antiepileptic/anticonvulsant activities

No. Scientic name PU Extract Seizure-inducing stimuli Animal models Doses (mg/kg) Treatment outcomes Refs.

1Acalypha fruticosa Ar CH PTZ, MES & INH Adult Swiss albino mice (25–30 g) 30–300 Protected the mice from PTZ and

MES-induced convulsions. Delayed the

latency of convulsions triggered by INH

[113]

2Ajuga integrifolia L HME PTZ & MES Swiss albino mice (20–30 g) 100–400 HME extract signiﬁcantly delayed the

latency onset of PTZ-induced convul-

sions at all doses (100, 200 & 400 mg/

kg) and decreased the duration of

tonic hind limb extension in the MES

model. Unlike BU and CH fractions, the

AQ fraction didn’t show any eﬀect on

latency and duration of convulsions at

all doses

[149]

3Allium sativum Bu AQ PLC Male adult Wistar rats (200–250 g) 100 & 300 The AQ extract demonstrated neuro-

protective potential in PLC-induced

neurodegeneration, mitigated the

prefrontal cortex (PFC) astrogliosis.

However, it didn’t decrease GLU and

other neurotransmitter levels

[150]

4Artemisia afra Wh HET PTZ Male BALB/c mice (22–30 g) 250–1000 Delay the mean onset of convulsion

and decrease the mean duration of

convulsions

[151]

5Asparagus africanus RAQ PLC Mus musculus Swiss mice (20–29 g) 63.5–254 Decreased the duration and number of

clonic and tonic convulsions. Increased

the latency time of onset of clonic and

tonic convulsions

[127]

6Azadirachta indica – – PTZ Sprague Dawley strain male rats 100 Decrease in seizures severity by

decreasing the mean onset time of

jerks and protecting the brain against

anoxic damage and oxidative stress

(OS) due to prolonged seizures

[152]

R HET PTZ & MES Albino rats of either sex (200–250 g) &

albino mice of either sex (30–50 g) 200–800 There was no signiﬁcant increase in the

mean duration of hind limb extension

in the test groups at all doses (200, 400

& 800 mg/kg). The HET root extract was

devoid of any anticonvulsant activity

in rodents

[153]

7Balanites aegyptica SB CH & HME PTZ, MES & PLC Male Albino Swiss mice (28–38 g) &

male Albino Swiss rats (200–225 g) 200 & 400 Both solvent extracts signiﬁcantly

suppressed hind limb extension and

delayed latency of myoclonic spasm

and clonic convulsions of mice at all

doses. Similarly, the CH (100 mg) and

HME (100 & 200 mg) extracts delayed

the latency to rearing with forelimb

clonus in rats

[154]

Page 12 of 37

Birhan Chinese Medicine (2022) 17:129

Table 4 (continued)

No. Scientic name PU Extract Seizure-inducing stimuli Animal models Doses (mg/kg) Treatment outcomes Refs.

8Buddleja polystachya L HME PTZ & MES S iss albino mice (27–33 gm) 100–400 The HME extract elicited a signiﬁcant

anticonvulsant eﬀect in MES (all doses)

and PTZ models (200 & 400 mg/kg).

The BU fractions showed a signiﬁcant

anticonvulsant eﬀect in both models. In

addition, the CH fractions were active

against seizure-induced by PTZ (200

& 400 mg/kg). While the AQ fractions

were devoid of any anticonvulsant

activities in both models

[155]

9Carissa edulis RB AQ PTZ, PIC, STR, NMDA, INH & AMP Swiss Albino mice (18–30 g) & Wistar

albino male rats (130–220 g) 150–600 The AQ fractions protected PTZ, STR,

and NMDA-induced seizures sig-

niﬁcantly at higher doses. But the AQ

fractions and sub-fractions showed no

eﬀect on MES-induced seizures

[156]

HET PTZ & MES Swiss Albino mice of either sex

(15–24 g) & White ranger cockerels of

either sex (30–41 g)

5–20 Delayed the mean onset of convulsions

in mice and chicks. It exhibited a dose-

dependent inhibition of the convulsion

induced by MES (90% protection at

20 mg/kg)

[104]

10 Clerodendrum myricoides L HET PTZ Male BALB/c mice (22–30 g) 300–1200 Unlike the solvent fractions, the crude

extract demonstrated a signiﬁcant

delay in the mean latency to onset of

seizures and decrease the duration

of convulsions in a dose-dependent

manner

[157]

11 Clutia abyssinica L HME PTZ & MES Male BALB/c mice (20–30 g) 400 & 800 Though the crude extract exhibited

insigniﬁcant dose-dependent delay on

the onset of a seizure, it improved the

survival of mice

[158]

12 Croton macrostachyus SB AQ PIC, STR, PTZ, INH & MES Adult male Mus musculus Swiss mice

(19–25 g) 13–135 The crude extract prevented the mice

from PIC, STR, PTZ, and MES-induced

seizures. It also delayed the onset of

INH-induced seizures

[140]

13 Indigofera arrecta L ME PTZ Zebraﬁsh with an AB or EK strain 30–300* The main constituent, idirubin, revealed

reduction of epileptiform discharges in

PTZ-treated zebraﬁsh larvae

[144]

14 Jatropha curcas LAQ PTZ & MES Male albino mice (25–30 g) 100–400 Protected the mice against the MES-

induced convulsion. While at 400 mg/

kg, it signiﬁcantly protected the mice

against PTZ-induced seizures

[134]

Page 13 of 37

Birhan Chinese Medicine (2022) 17:129

Table 4 (continued)

No. Scientic name PU Extract Seizure-inducing stimuli Animal models Doses (mg/kg) Treatment outcomes Refs.

15 Maytenus heterophylla L, R & SB ME PIC White Swiss albino mice (20–24 g) 50–200 The stembark extract signiﬁcantly

suppressed convulsions induced by PIC

better than the leaf and root extracts.

It also oﬀered up to 62.5% protection

against seizure at 200 mg/kg which

was signiﬁcant (p < 0.05) as compared

to diazepam

[159]

16 Nicotiana tabacum Ar AQ & HME PTZ Random breed albino male mice

(18–24 g) 100 Both extracts decreased the onset and

severity of seizures (but it is statisti-

cally insigniﬁcant as compared to the

negative control group). Both extracts

decreased the mortality of PTZ-treated

mice

[160]

17 Olea europaea – – PTZ Mice weighing (25–30 g) 20 The active constituent of Olea europaea

leaf, oleuropein (20 mg/kg), caused a

signiﬁcant increase in seizure latency

and a signiﬁcant decrease in the whole

body seizure

[161]

18 Opuntia ﬁcus-indica Fl HME PTZ, MES & STR Swiss albino mice (20–25 g) 250 & 500 Protect the mice against PTZ, MES, and

STR-induced seizures [135]

19 Pentas schimperiana RB HME PTZ & MES Swiss albino mice (20–30 g) 100–400 The BU and ME fractions signiﬁcantly

inhibited the PTZ and MES-induced

seizure at 400 mg/kg

[162]

20 Pterolobium stellatum L AQ & HME PTZ & MES Swiss albino mice (25–32 g) 100–400 The HME extract exhibited a dose-

dependent increase on the latency

onset of seizure against PTZ. In

addition, both HME and AQ fractions

demonstrated a dose-dependent

reduction in duration of hind limb

tonic extensions in the MES model and

myoclonic seizure in the PTZ model at

400 mg/kg

[163]

21 Ruta chalepensis Ar ET PTZ Male Swiss albino mice (25–30 g) 10–1000 Delayed the onset of seizures and a

dose-dependent suppression in the

tonic phase and mortality induced by

PTZ was noticed

[164]

22 Securidaca longepedunculata RAQ STR & PIC Albino mice of either sex (20–25 g) 100–400 The extract elicited dose-dependent

increase in onset of convulsion and

prolongation of the cumulative time

spent in the open arms of the elevated

plus maze and Y maze compared with

the control

[165]

Page 14 of 37

Birhan Chinese Medicine (2022) 17:129

Table 4 (continued)

No. Scientic name PU Extract Seizure-inducing stimuli Animal models Doses (mg/kg) Treatment outcomes Refs.

SB AQ PTZ, MES & AMP Swiss albino mice of either sex

(18–25 g) 50–200 The extract aﬀorded signiﬁcant protec-

tion against the mice treated with PTZ

(50 & 100 mg/kg) and MES (50 mg/kg).

It didn’t attenuate AMP induced seizure

though it prolonged the onset of con-

vulasions at 100 and 200 mg/kg

[166]

23 Sida rhombifolia Wh ME PTZ & MES Swiss albino mice of either sex

(25–30 g) 100–400 The ME crude extract signiﬁcantly

reduced the duration of seizures at all

doses

[136]

24 Withania somnifera S & R ET PTZ & MES Albino Wistar rats of either sex

(150–200 g) 100–300 The extracts signiﬁcantly suppressed

hind limb tonic extension and postictal

depression in MES test groups at

300 mg/kg. Moreover, a signiﬁcant

reduction in the mean duration of

hind limb tonic ﬂexion, hind limb tonic

extension, clonus, and stupor in PTZ

test groups

[110]

25 Xanthium stramonium Wh PE PTZ & MES Albino Wister albino rats (150–200 g) 250 & 500 The crude extract reduced the duration

of convulsions. It also delayed the

onset of myoclonic spasm and clonic

convulsion in albino Wister rats

[167]

26 Zingiber oﬃcinale Rh HET PTZ Wild type adult zebraﬁsh of the AB

strain 60bThe active constituent of the extract,

6-gingerol (6-GIN), eﬀectively inhibited

PTZ-induced seizures

[168]

Adult male Swiss mice 25–200 It signiﬁcantly increased the onset

time of myoclonic seizures at a dose of

25–100 mg/kg and signiﬁcantly pre-

vented generalized clonic seizures

[169]

PU plant parts used, L leaf, S stem, SB stembark, R root, RB rootbark, Wh whole plant, Ar Aerial part, Bu bulbs, Fl ower and Rh rhizome Seizure-inducing agents PIC picrotoxin, STR strychnine, PTZ pentylenetetrazol,

INH isonicotinic hydrazide acid and MES maximal electroshock, PLC pilocarpine, AMP 4-aminophylline, and NMDA N-Methyl-D-aspartate. Extraction solvents AQ aqueous, CH chloroform, BU butanol, ET ethanolic, HET

hydroalcoholic/hydroethanolic, ME methanolic, HME hydromethanolic, and PE petroleum ether

a and brepresented the plant extract doses given in µM and µg/mL, respectively

Page 15 of 37

Birhan Chinese Medicine (2022) 17:129

In vivo pharmacological activities ofcrude extracts

andsolvent fractions

Single stimuli-induced seizure model PTZ is routinely

used as a stimulus to induce convulsions in diﬀerent ani-

mal models by inhibiting the GABAergic neurotransmis-

sion [170]. PTZ-induced seizures are characterized by an

initial ‘absence-like’ immobility, followed by brief myo-

clonic jerks, sustained myoclonus, and ﬁnally GTCS with

a loss of the righting reﬂex. e subcutaneous adminis-

tration of PTZ is often used to induce a seizure in mice

[171] that can be employed to assess the anticonvul-

sant activity of MPs. e whole plant and leaf extract of

Artemisia afra are traditionally used for the treatment

of epilepsy in Ethiopia and South Africa, respectively

(Table3) [105]. Kediso etal. [151] investigated the anti-

convulsant eﬀect of the HET and solvent fractions of

Artemisia afra whole part against PTZ-induced seizure

in mice. Unlike the solvent fractions, the HET crude

extract triggered a signiﬁcant delay in the mean onset

of convulsions (504.833 ± 62.835 s, 551.833 ± 74.69 s,

and 808.333 ± 64.8s) and a decrease in the mean dura-

tion of convulsions (17.000 ± 1.88 s, 13.000 ± 1.8 s and

7.833 ± 1.07s) at the respective doses of 250, 500 and

1000mg/kg. e observed activity of the crude extract

might be attributed to the presence of multiple second-

ary metabolites in the herb. Clerodendrum myricoides is

another MP whose leaf extract is traditionally used as an

anticonvulsant in Ethiopia, Kenya, and South Africa [100,

119]. Owing this, the anticonvulsant activity of the HET

and solvent fractions of the leaf extract was assessed via

mice experiencing PTZ-induced seizures [157]. e HET

crude extract of Clerodendrum myricoides at 300, 600 and

1200mg/kg signiﬁcantly delayed the mean latency in the

onset of seizures (299.33 ± 30.129s , 387.167 ± 27.6s and

417.833 ± 31.9s, respectively) and decrease in the dura-

tion of convulsions (27.333 ± 1.585s, 16.833 ± 1.537s and

10.50 ± 0.671s, respectively) in a dose dependent manner

as compared to the control group. On the other hand, the

solvent fractions of Clerodendrum myricoides didn’t show

signiﬁcant anticonvulsant eﬀect in the model.

Ruta chalepnesis is known for its antiepileptic activities

in the traditional folklore of Ethiopia, Morocco, and Mex-

ico [125, 126]. e ET extracts of the aerial parts of Ruta

chalepnesis were assessed by using PTZ-induced seizure

and a dose-dependent suppression in the tonic phase

was observed, moreover, it reduced the mortality trig-

gered by PTZ in the experimental animals. Azadirachta

indica is employed in the traditional healthcare system

of Ethiopia and India to treat epilepsy [128]. Kumar etal.

[152] compared the antiseizure activities of Valproic acid

(VPA) and Azadirachta indica on PTZ-induced kindling

in Sprague Dawley strain male rats at 200 mg/kg and

100mg/kg, respectively. A decrease in the mean onset

time of jerks, clonus, and extensor phases was observed

in VPA and Azadirachta indica treated groups. Moreo-

ver, an increase in glutathione reductase activity and a

decrease in the activity of lipid peroxidation enzymes,

glutathione S-transferase activity, catalase, and nitric

oxide was observed in the same group, asserting the pro-

tective eﬀects of VPA and Azadirachta indica against

anoxic damage and OS of the brain due to prolonged

seizures. Overall, Azadirachta indica demonstrated bet-

ter preventive eﬀects than VPA on PTZ-induced chemi-

cal kindling in rats. Asparagus africanus is a widely used

plant in TM as an anti-inﬂammatory, antioxidant, for

the treatment of CNS disorders including epilepsy. e

anticonvulsant activity of the root decoction of Aspara-

gus africanus was evaluated in PLC-induced SE in Mus

musculus Swiss mice. It increased the onset time of

tonic–clonic convulsions and decreased the duration and

number of tonic–clonic convulsions at doses of 63.5, 127,

and 254 mg/kg. e anticonvulsant activity of Aspara-

gus africanus emanated from modulation of GABA

(increase), GABA-T, TNF-α (decrease) levels, and inhibi-

tion of OS in the brain [127].

Dual stimuli-induced seizure models MES is the second

most commonly used seizure-inducing stimuli in diﬀer-

ent animal models of epilepsy next to PTZ. It is conveni-

ent to assess GTCS that can be reproduced with reliable

endpoints [172]. e use of two common stimuli, PTZ

and MES, in diﬀerent animal models will help to better

understand the pharmacological eﬀects and the MOA of

anticonvulsant agents. Carissa edulis is commonly used

for the treatment of epilepsy in Africa especially in Ethio-

pia, Nigeria, South Africa, Uganda, Malawi, and Kenya

[104–108]. Owing to this, the anticonvulsant activity

of the rootbark of Carissa edulis was investigated using

PTZ-induced seizure in mice and the MES test in chicks.

It exhibited a suboptimal level of inhibition against sei-

zure as compared to benzodiazepine (BZP) (100%) in the

mice model. Moreover, the crude extract elicited 90%

protection as compared to phenytoin (100%) at 20mg/kg

in convulsions induced by MES in chicks signifying the

beneﬁcial eﬀect of Carissa edulis for the management of

epilepsy and related symptoms [104]. Clutia abyssinica is

claimed to have antiepileptic activity in traditional herbal

medicine folklore of Ethiopia and Rwanda [129]. Although

the HET leaf crude extract of Clutia abyssinica improved

the mean survival time of epileptic mice, the recorded

mean time of hind limb extension was not signiﬁcant at

400 and 800mg/kg as compared to the negative control

group [158]. Leaves of Jatropha curcas have been used by

TH of Ethiopia and Nigeria for the management of epi-

lepsy. Bolanle et al. [134] examined the anticonvulsant

activity of AQ leaf extract of Jatropha curcas in PTZ- and

Page 16 of 37

Birhan Chinese Medicine (2022) 17:129

MES-induced seizure models. e crude extract delayed

the onset of tonic leg extension and the seizure-induced

mortality was inhibited in mice. Moreover, it signiﬁcantly

(p < 0.05) protected mice from MES-induced seizure at

100, 200 and 400mg/kg. at a higher dose, 400mg/kg, it

also signiﬁcantly inhibited PTZ-induced convulsions.

Pentas schimperiana is a MP used in Ethiopian TM for

the treatment of epilepsy. Fisseha etal., [162] assessed

the HME rootbark crude extract and CH, BU, and AQ

fractions of Pentas schimperiana using PTZ and MES-

induced seizure models at doses of 200 and 400mg/kg.

As compared to the control group, the ME and BU frac-

tions, at 400mg/kg, demonstrated signiﬁcant (p < 0.001)

anticonvulsant activities in both models. In addition,

the CH fraction exerted signiﬁcant (p < 0.001) seizure

control in PTZ treated mice whereas the aqueous frac-

tion was devoid of signiﬁcant antiepileptic activities in

both models. In general, the alkaloids, ﬂavonoids, sapo-

nins, tannins, phenols, steroids, and terpenoids present

in the rootbark may be ascribed to the observed seizure

control in mice. Sida rhombifolia is a plant commonly

prescribed for the treatment of epilepsy by the THs of

Ethiopia and India [136]. e ME crude extract of the

whole part of Sida rhombifolia was examined PTZ and

MES-induced seizure in mice at 100, 200, and 400mg/

kg. e result reiterated that the ME crude extract of

100, 200, and 400 mg/kg signiﬁcantly suppressed the

duration of seizure as compared to the control group in

both models. Xanthium stramonium is a famous MP in

China due to its widespread healthcare prominence. It

is also used for the treatment of epilepsy in Ethiopia and

India [141]. Owing to this, Kumar etal. [167] screened

the anticonvulsant activity of the PE whole plant extract

of Xanthium stramonium against PTZ and MES-induced

seizure models in albino Wistar rats at a dose of 250 and

500mg/kg. It increased the latency onset of myoclonic

spasms and clonic convulsions in PTZ-treated groups. In

addition, it also reduced the mean duration of the exte-

rior phase signiﬁcantly as compared to the control group

in the MES test. e root of Azadirachta indica was used

in herbal formulations prepared to treat epilepsy in dif-

ferent countries. e invivo anticonvulsant assessement

done on PTZ-induced seizure in mice and MES-induced

seizure in Albio rats indicated that the ET root extract

has no signiﬁcant eﬀect on the mean duration of limb

extension, mean onset of convulsions and mean number

of convulsions at a dose of 800mg/kg as compared to the

control group [153].

Multiple stimuli-induced seizure models Multiple stim-

uli-induced seizure models provide better information

about the eﬀect of drugs or a plant extract in the target

experimental animals. e depth and breadth of data

obtained in such multiple seizure models can shed light

on the diﬀerent aspects of the plant extract under consid-

eration: MOA, potential targets for antiepileptic interven-

tions, possible bioactive compounds, etc. In addition to

PTZ and MES, one or more of the following stimuli such

as INH, PIC, PLC, NMDA, STR, AMP, and BIC are used to

induce convulsions (in experimental animals) in epilepsy

research. Traditional herbalists of Ethiopia, Tanzania,

and Kenya [113, 114] have faith in the curative eﬀect of

Acalypha fruticosa for the treatment of epilepsy. Govindu

et al., [113] assessed the anticonvulsant activity of the

CH crude extracts of the aerial parts of Acalypha fruti-

cosa using PTZ, MES, and INH-induced seizures in Swiss

albino mice at doses of 30, 100, and 300mg/kg. e result

conﬁrmed the potential of the crude extract to suppress

seizures triggered by MES in a dose-dependent pattern.

At 300mg/kg, as compared to diazepam (4mg/kg) the

extract demonstrated more pronounced anticonvulsant

activity. It also inhibited the PTZ-induced seizures better

than the positive control, phenobarbitone sodium. While

in the INH model, it delayed the onset of convulsions in

a dose-dependent manner but failed to protect the mice

from seizure-induced mortality. Balanites aegyptiaca is

used traditionally in Ethiopia, Mali, Saudi Arabia [116,

117], and India to treat epilepsy. Hence, HMET and CHL

extract of stembark of Balanites aegyptiaca were assessed

using PTZ, MES-induced convulsions, and PLC-induced

SE in rats [154]. Both the HME and CH extract at 200 and

400mg/kg signiﬁcantly delayed the onset of myoclonic

spasm and clonic convulsions as well as signiﬁcantly

reduced the duration of hind limb extension in PTZ and

MES models. In the PLC model, the CH extract (100mg)

and HME extract (100 and 200mg) delayed the latency to

rearing with forelimb clonus signiﬁcantly.

Carissa edulis is popular in African countries such as

Ethiopia, Nigeria, South Africa, Uganda, Malawi, and

Kenya [104–108] for its beneﬁcial eﬀect in the manage-

ment of epilepsy by herbalists or TH. e anticonvul-

sant activity of the AQ fractions (150, 300, and 600mg/

kg) and sub-fractions (250, 500, 500, and 1000 mg/kg)

of the rootbark extract was examined using PTZ, PIC,

NMDA, INH, STR, and AMP-induced seizures in mice.

e AQ fraction and sub-fractions suppressed 50% and

16.67% of PTZ-induced convulsions. Similarly, the AQ

fraction experienced 33.33% and 16.67% protection

against strychnine and NMDA seizure models, respec-

tively. Moreover, the AQ fractions elicited 66.67–33.33%

protection against AMP-induced seizures at doses of

150 and 600mg/kg. However, the AQ fractions and sub-

fractions did not aﬀect MES-induced seizures. Croton

macrostachyus is a common tree used to treat epilepsy in

Ethiopia and Cameron [140]. Bum etal. [140] employed

MES, STR, PTZ, PIC, and INH-induced seizure models

Page 17 of 37

Birhan Chinese Medicine (2022) 17:129

to evaluate the anticonvulsant activity of AQ stembark

extract of Croton macrostachyus in Mus musculus Swiss

mice. e extract protected 60, 80, 80, and 80% of mice

from MES, PTZ, PIC, and STR-induced convulsions,

respectively even at an initial dose of 34 mg/kg. It also

increased the latency onset of seizures in INH-treated

mice. Overall, the result suggested that Croton macros-

tachyus may have a promising eﬀect in secondary GTCS

and primary generalized seizures in humans. Opuntia

ﬁcus-indica commonly known as cactus pear is used in

the treatment of epilepsy in Ethiopia and India [135]. e

invivo anticonvulsant activity of the ﬂower ME extract

was assessed using Swiss Albino mice. e ME extract

produced signiﬁcant inhibition against PTZ, MES, and

STR-induced convulsion at 250 and 500mg/kg. ere

was an increase in noradrenaline and dopamine level in

the mice’s brains due to the avoidance of MES-induced

convulsions.

In vivo pharmacological activities ofisolated compounds/

constituents

Indigofera arrecta is a common MP used by the indig-

enous inhabitants of Ethiopia, Nigeria, Congo, and

South Africa [100, 122]. Bioassay-guided fractionation of

Indigofera arrecta in zebraﬁsh model results in the iden-

tiﬁcation of indirubin and 6-bromoindirubin-3ꞌ-oxime

(BIO-acetoxime), compounds with glycogen synthase

kinase (GSK)-3 inhibition activity demonstrated signiﬁ-

cant anticonvulsant activity in PTZ-induced seizure in

zebraﬁsh larvae. Moreover, they also showed signiﬁcant

antiseizure activity in the PLC rat model limbic seizure

and the 6-Hz refractory seizure mouse model, demon-

strating GSK-3 inhibition as a potential therapeutic tar-

get for epilepsy. Olea europaea is among the known MPs

used for the management of epilepsy in Ethiopia and

Kenya [108]. Oleuropin, a secondary metabolite extracted

from the leaves of Olea europaea, elicited a signiﬁcant

increase in seizure latency and a signiﬁcant decrease in

total frequencies of head ticks, head and upper limbs sei-

zures, frequent spinning and jumping, and tonic seizures

in PTZ kindling of seizure in mice. Oleuropin treated

groups (20 mg/kg) showed downregulation of genes

responsible for the expression of IL-1 without change in

GLT-1 levels. e signiﬁcant antepileptic activity of ole-

uropin may be attributed to its antioxidant and antiin-

ﬂammatory activities making it an ideal pharmacophore

for the synthesis of AEDs. Zingiber oﬃcinale is another

most frequently used medicinal herb in diﬀerent parts of

the world. For instance, in Ethiopia and Japan Zingiber

oﬃcinale is used for the management of epilepsy [137].

Its HET extract of rhizome has demonstrated anticonvul-

sant activity in rodent seizure models [169, 173]. Gawel

etal., [168] also proved the anticonvulsant eﬀect of ME

crude extract using a PTZ-induced seizure in zebraﬁsh

larvae. Inspired by its activity, the group also isolated

the major constituent of Zingiber oﬃcinale rhizome,

6-gingerol (6-GIN) that exerted dose-dependent antisei-

zure activity in PTZ-induced hyperlocomotion assay in

zebraﬁsh larvae. Rigorous experimental procedures and

molecular docking analysis in human NR2B-containing

NMDA receptors suggested that the antiepileptic activ-

ity of 6-GIN may be partly mediated by restoring the bal-

ance between GABA and GLU in the epileptic brains.

In general, the in vivo anticonvulsant activity of the

aforementioned MPs resonated the potentials of herbal

formulations in the healthcare system of diﬀerent coun-

tries. Although most of the antiepileptic MPs claimed by

THs were not screened for their anticonvulsant eﬀects

through suitable seizure models, this review partly doc-

umented the strong association that exist between the

indeginous knowledge of THs and pharmacological

activities of MPs used to treat epilepsy and related symp-

toms in Ethiopia and other parts of the world.

Toxicity proles ofantiepileptic oranticonvulsant

medicinal plants

Acute toxicity proles ofmedicinal plants

Acute toxicity study of plant extracts is performed to

the assess the potential inherent toxicity that may be

displayed in a short period of time upon a single dose

exposure mostly via the oral route as it is considered as

a viable route for accidental human exposure for haz-

ardous substances and it allows for hazard classiﬁcation

of test substances [174]. e leaf part of Artemisia afra,

Azadirachta indica, Brucea antidysenterica, Buddleja

polystachya, Eucalyptus Globulus, Gloriosa superba,

Maytenus heterophylla, Nicotiana tabacum, and Oci-

mum lamiifolium are commonly used for the preparation

of remedies used to treat epilepsy and related symptoms

in Ethiopia. e acute toxicity studies conducted in the

crude extracts, essential oils and bio-oils recapped the

absence of gross behavioral, physical changes and signs

of overt toxicity such as lacrimation, urination, mus-

cle weakness and convulsions in diﬀerent animal mod-

els [175–181]. As depicted in Table5, relatively higher

LD50 value greater than 5000mg/kg of body weight were

recorded for Artemisia afra, Azadirachta indica, Gloriosa

superba, and Nicotiana tabacum extracts. In addition,

the EO of Eucalyptus Globulus, and HET extract of May-

tenus heterophylla 2.5mL/kg and > 1200mg/kg, respec-

tively demonstrating the safety proﬁles of single dose of

the plant extracts. Furthermore, the roots of Asparagus

africanus, Biophytum umbraculum, Capparis tomentosa,

and Withania somnifera are believed to be rich in bioac-

tive chemicals characterized by attenuating convulsions.

eir crude extracts and solvent fractions were devoid

Page 18 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 Acute toxicity proﬁles of some MPs employed in the treatment of epilepsy and related symptoms

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

1Ajuga integrifolia R HME Swiss albino male mice (20–30 g) 2000 > 2000 Neither mortality of mice nor

any signs of toxicity (behavio-

ral, neurological, autonomic, or

physical changes) was observed at

2000 mg/kg of body weight

[189]

2Allium sativum Bu AQ Wistar rats (⁓115–126 g) 100, 1000, 2500 & 5000 > 5000 No death was recorded at all doses.

The rats treated with 5000 mg/

kg of body weight experienced car-

diac problem and disorientation

[190]

3Artemisia abyssinica Ar ET Swiss albino mice (25–30 g) 500, 1000 & 3000 > 3000 The mice did not show visible

toxicity, although at 3000 mg/kg

a decreased in locomotor activity

was observed

[191]

4Artemisia afra LAQ Female adult Swiss albino mice

(25–30 g) 200, 700, 1200, 2200, 3200, 4200

&5000 > 5000 Mild toxicities like anxiety and

piloerection were observed at

higher doses (≥ 3200 mg/kg) that

disappear in the wash out periods.

No mortality in mice was recorded

at all doses

[175]

L ET, DCM & HX Swiss albino mice (20–22 g) 1000, 2000 and 2500 > 2500 Loss of appetite, hypoactivity,

lethargic, dizziness that disap-

peared in the washout period was

noticed in mouse treated with

DCM extract at 2500 mg/kg

[192]

5Asparagus africanus R HET & BU Swiss albino mice (20–25 g) 1000, 3000 & 5000 > 5000 There was no dose-dependent

behavioral change, weight change

and mortality in mice treated single

dose BUT fraction orally

[182]

6Azadirachta indica LAQ Female BALB/c mice (average mass

of 30 g) 1250, 2500 & 5000 > 5000 The mice treated with the extract

were devoid of weight/hair loss,

allergy, or other symptoms of

discomfort

[176]

7Balanites aegyptiaca SB AQ Fishes 17.5, 20, 22.5 & 25a⁓18.99–

20.72aB. nurse, L. intermedius and L. bynni

ﬁsh species treated with the extract

suﬀered from the debilitating toxic

eﬀect

[193]

8Biophytum umbraculum R AQ, BU & CH Female Swiss Albion mice (22–30 g) 2000 > 2000 There was no behavioral change,

weight change and mortality in

mice treated single dose of all

fractions

[183]

Page 19 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

9Brucea antidysenterica L AQ, ME & CH Swiss albino mice (27–36 g) 500, 1000 & 2000 – The extracts lack visible signs of

acute toxicity and mice fatality till

the dose of 1000 mg/kg. But, at

the dose of 2000 mg/kg it caused

mortality in all mice with in 24 h

[194]

10 Buddleja polystachya L HME Female Sprague–Dawley rats

(150–200 g) 2000 – There was no visible sign of skin

reaction, inﬂammation, erythema,

irritation or redness, and any

adverse reaction in rats

[177]

11 Calpurnia aurea L AQ & HME Female Swiss albino mice 5000 > 5000 The mice were devoid of gross

behavioral or physical changes

and signs of overt toxicity such

as lacrimation, urination, muscle

weakness and convulsions

[186]

12 Capparis tomentosa R HME Male Swiss Albino mice (25–38 g) 2000, 3000 & 5000 > 2000 The mice showed signs of slight

rigidity and sleepy activity at

higher doses of extract (3000 and

5000 mg/kg). No mortality was

recorded at all doses

[184]

13 Carissa edulis LAQ Wistar albino rats of either sex 2000 > 2000 The rats showed no gross behavio-

ral or physical changes and signs of

overt toxicity

[195]

RB ET Wistar albino rats (124–220 g) &

Swiss mice (16–35 g) 10, 100 & 1000 ⁓3808 None of the mice and rats orally

treated with the extract manifested

signs of toxicity except death at

the dose of 5000 mg/kg (in both

species)

[187]

14 Caylusea abyssinica L HME Male Swiss albino mice (20–30 g) 2000 > 2000 The mice didn’t experience any

behavioral, neurological, auto-

nomic or physical changes

[196]

15 Clerodendrum myricoides RAQ Swiss albino mice of either sex

(25–30 g) 1134 – Behavioral changes such as hor-

ripilation, diﬃculty in breathing,

grooming, and asthenia followed

by death was noticed in mice

treated with 1134 mg/kg

[197]

16 Croton macrostachyus R HME Female Swiss Albino mice (25–28 g) 2000 & 5000 > 5000 The mice showed no visible signs

of lacrimation, loss of appetite,

tremors, hair erection, salivation,

diarrhea and convulsion

[198]

Page 20 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

SB AQ & HME Female Swiss albino mice 5000 > 5000 The mice were devoid of gross

behavioral or physical changes

and signs of overt toxicity such

as lacrimation, urination, muscle

weakness and convulsions

[186]

SB HME, AQ & ETAc Female Swiss albino mice 2000 > 2000 None of the mice treated with

crude extract or solvent fractions

showed problems in breathing,

alertness, motor activity, restless-

ness, diarrhea and convulsions

[199]

17 Cucumis ﬁcifolius R HME & CH Swiss albino mice (25–30 g) 125, 250, 500 & 2000 > 2000 There were no mortality and signs

of overt toxicities at a dose of

2000 mg/kg of body weight

[200]

18 Echinops kebericho Tu EO Swiss albino mice (18–26 g) 300 & 2000 > 2000 Though the mice showed piloerec-

tion, muscle spasm and apathy

immediately after administra-

tion, there were no signiﬁcant

treatment-related morbidities

[201]

Tu AQ Wistar albino rats (250–350 g) 300, 2000 & 5000 > 5000 The rats experienced piloerection,

muscle twinge, and lethargy after

the treatment with the extract

(5000 mg/kg) which disappeared

after 5 h. But, there were no

treatment related morbidity and

mortality at 5000 mg/kg

[202]

19 Embelia schimperi Fr HET Female Wistar rats (180–210 g) 400, 1000, 2000, 3000, 4000 & 5000 > 5000 The extract didn’t elicit prominent

signs of toxicity and any mortality

in rats in the study period

[203]

20 Eucalyptus Globulus L EO Swiss albino mice of either sex

(23–30 g) 2, 2.5, 3 & 3.5b2.5bThe mice treated with the essential

oil showed restlessness, debilita-

tion, reduced food and water

intake and piloerection which

disappeared in the washout period

after treatment with ≥ 2.5 mL/kg

[178]

21 Fagaropsis angolensis SB HME, AQ, BU & CH Adult male Swiss albino mice

(25–30 g) 2000 ≥ 2000 Neither mortality nor any signs

of toxicity were observed in mice

treated with both extracts at

2000 mg/kg body weight

[204]

Page 21 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

22 Foeniculum vulgare Fr ET Swiss labial mice (25–28 g) 500, 1000 & 3000 ≥ 3000 The extract didn’t trigger mortality

of mice and overt toxicity except

reduced locotmotor activity and

piloerection at 3000 mg/kg of body

weight

[205]

23 Gloriosa superba LAQ White male Wistar rats (200–250 g) ⁓121, 364, 1091 & 3274 > 1500 The rats experienced treated with

colchicine of standardized Gloriosa

superba extract showed no visible

sign of overt toxicity

[206]

L HME Non-pregnant Wistar rats

(120–140 g) 200 & 5000 > 5000 There were no visible overt signs of

toxicity at 5000 mg/kg. No morbid-

ity or mortality was observed in the

rats treated groups at both doses

[179]

24 Justicia schimperiana L HME Swiss albino mice (18–30 g) 2000 > 2000 The extract didn’t trigger signs of

overt toxicity. Moreover, no mortal-

ity of mice was recorded in the

study period

[207]

L HME Female adult Wistar rats (180–

200 g) 2000 > 2000 Rats showed no formation of

edema or erythema. No signs of

toxicity as well as no mortality were

noted during the study period

[208]

25 Maytenus heterophylla L HET Male CD-6 mice (35–40 g) 1200 > 1200 The mice treated with the extract

were devoid of physical and behav-

ioral changes at 1200 mg/kg

[180]

26 Maytenus senegalensis RB ET Swiss albino mice (18–22 g) 200, 300, 400, 800 & 1600 > 1600 The mice treated with the extract

were devoid of physical and behav-

ioral changes at 1600 mg/kg

[209]

SB HET Theiller’s albino mice of either sex 1000, 2000, 3000, 4000 & 5000 > 5000 The mice treated with the extract

were devoid of physical and behav-

ioral changes at 5000 mg/kg

[210]

L & S HET Male CD-6 mice (35–40 g) 1200 – The mice treated with leaf extract

exhibited some signs of overt toxic-

ity. In addition, the stem extract

caused pronounced toxicity at

1200 mg/kg

[180]

27 Myrica salicifolia R HME Non-pregnant female mice 2000 > 2000 There are no visible signs of

overt toxicity and mortality in

mice treated with the extract at

2000 mg/kg

[211]

Page 22 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

28 Nicotiana tabacum L Bio-oil Female Wistar rats (130–140 g) 5000 > 5000 The rats exhibited no signiﬁcant

change in the body weight and

behavior. In addition, there was no

mortality of rats in the study period

[181]

29 Ocimum lamiifolium L ME Swiss albino mice (27–36 g) 500, 1000 & 2000 ≥ 2000 The crude extract didn’t trigger

gross visible signs of acute toxicity

such as urination, hair erection,

lacrimation, and reduction in feed-

ing activity

[194]

30 Olea europaea LET Wistar rats of either sex (150–200 g) 2000 ≥ 2000 Oral administration of the extract

didn’t cause any mortality or sign

of toxicity at 2000 mg/kg of body

weight during the study period

[212]

31 Opuntia ﬁcus-indica S HET White Sprague Dawley rats either

sex 500, 1000 & 2000 – The rats exhibited no genotoxicity

at all treatments regimens even at

the maximum dose of 2000 mg/kg

[213]

Se HX (ﬁxed oil) Mus musculus mice (20–30 g) 10, 20, 30, 40, 50, 60 & 70b43bThe mice suﬀered from immediate

agitation and behavioral perturba-

tions with temporary writhing,

followed by a quiet attitude period

and sedation

[214]

32 Pentas schimperiana L AQ & HME Swiss Albino mice of either sex

(20–33 g) 1000, 2000 & 5000 > 4000 The mice experienced no visible

change in behavior such as rest-

lessness, motor activity, breathing

and diarrhea. Moreover, there was

no mortality recorded at 5000 mg/

[215]

33 Podocarpus falcactus Ap AQ Female Sprague Dawley rats

(260–300 g) 2000 > 2000 The rats showed neither mortality

nor gross behavioral changes and

mortality at 2000 mg/kg of body

weight

[216]

34 Ruta chalepensis Ar ET Male Swiss albino mice (25–30 g) 1600, 3000 & 5000 > 5000 The extract didn’t trigger mortality

nor macroscopic tissue injury or

weight loss at 5000 mg/kg per

body weight

[164]

35 Rhus vulgaris SB AQ, Female Swiss albino mice (18–26 g) 50, 300 & 2000 > 2000 The mice were devoid of changes

in general appearance and behav-

ioral patterns. In addition, there was

no mortality or gross pathology in

any organ at necropsy

[217]

Page 23 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

36 Securidaca longepedunculata L, S & R AQ & ME/CH (1:1) Swiss female mice (20–22 g) 50, 300 & 2000 > 2000 The AQ total extracts of leaves and

stembark did not show any change

in behavior following adminis-

tration of the crude extracts at

2000 mg/kg of body weight

[218]

37 Sida rhombifolia Ar ET Adult male Wistar albino rats

(180–220 g) 2000 > 2000 There were no visible overt signs of

toxicity and mortality in rats treated

with 2000 mg/kg of the extract

[219]

Ar HME Albino Wistar rats (102–134 g) 4000, 8000, 12000 & 1600 > 8000 The rats exhibited slight changes

in general behavior such as sow

response to external stimuli,

stretching and sluggishness

[220]

RAQ Sprague Dawley rats of either sex

(130–190 g) 5000 > 5000 The rats experienced neither overt

toxicity signs nor mortality at a

single dose of 5000 mg/kg

[221]

38 Syzygium

guineense

L HME Wistar rats of either sex (120–140 g) 2000 & 5000 > 5000 In the acute toxicity study, rats

treated with 2000 mg/kg and

5000 mg/kg showed no toxico-

logical signs observed on behavior,

gross pathology, and body weight

of rats

[179]

39 Teclea nobilis Wh HME & AQ Male Swiss mice (⁓20 g) 1000, 2000, 3000, 4000 & 5000 > 5000 The extract was devoid of any overt

toxicities at 5000 mg/kg of body

weight. Moreover, there was no

mortality recorded in the study

period

[222]

40 Vernonia amygdalina L AQ & HME Female Swiss albino mice 5000 > 5000 The mice exhibited no signs of

overt toxicity such as lacrimation,

urination, muscle weakness, seda-

tion and convulsions at 5000 mg/

[186]

L AQ & ET Albino Wistar rats (200–250 g) 2000 > 2000 The extracts triggered no sig-

niﬁcant eﬀect on the biochemical

and hematological parameters of

treated rats (no lesions were also

observed in the liver and kidneys

histologically)

[223]

41 Withania somnifera R ME Wistar rats 5000, 1000 & 2000 > 2000 The rats didn’t experience any

organ atrophy, hypertrophy, and

degenerative or inﬁltrative lesions

even at 2000 mg/kg

[185]

Page 24 of 37

Birhan Chinese Medicine (2022) 17:129

Table 5 (continued)

No. Scientic name PU Extract Animal models Acute toxicity studies Refs.

Doses (mg/kg) LD50 (mg/kg) Treatment outcomes

42 Zingiber oﬃcinale R HX (ﬁxed oil), EO Swiss albino mice (23–26 g) and

Wistar rats (150–170 g) 0.02, 0.04, 0.06, 0.08 and 0.1b mL/kg

for ﬁxed oil; 0.2, 0.4, 0.6, 0.8, 1.0, 2.0,

4, 6, 8 and 10b for EO

– Observed cardinal signs of toxicity

for both oils were decreased motor

activity, convulsion and paralysis. In

addition, mortality of experimen-

tal animals was noticed in both

ﬁxed-oil (0.2 mL/kg) and EO treated

group

[224]

PU plant parts used, Ap apex, L leaf, S stem, Se seeds, SB stembark, R root, RB rootbark, Ar Aerial part, Bu bulbs, Tu tuber and Rh rhizome, Extraction solvents, AQ aqueous, CH chloroform, BU butanol, DCM dichloromethane,

ET ethanolic, ETAc ethyl acetate, HX hexane, HET hydroalcoholic/hydroethanolic, ME methanolic, HME hydromethanolic, PE petroleum ether and EO essential oil

a and brepresented the plant extract doses and LD50 values are given in mg/L and mL/kg, respectively

Page 25 of 37

Birhan Chinese Medicine (2022) 17:129

of any inherent acute toxicity symptoms at a single dose

greater than 2000 mg/kg body weight [182–185]. e

AQ and HME stembark extract of Croton macrostach-

yus (LD50 > 5000) and the ET rootbark crude extract of

Carissa edulis, (LD50 ⁓3,808) were found to be safe [186,

187], consequently, the experimental animals manifested

neither visible signs of lacrimation, loss of appetite,

tremors, hair erection, salivation, diarrhea and convul-

sion nor mortality in the study period at the estimated

doses equivalent to LD50 values. According to Globally

Harmonized Classiﬁcation System (GHCS) for chemical

substances and mixtures, synthetic chemicals and plant

extracts having an LD50 > 2000mg/kg of body weight is

considered as safe [188]. is reiterated the relative safety

proﬁles of most MPs used to treat epilepsy and related

symptoms in Ethiopia.

Subacute toxicity proles ofmedicinal plants

Acute toxicity studies provide preliminary data about

the safety proﬁles of a single dose of chemical agents

[225], consequently, it is considered as shallow and

sometimes misleading. Better information about the

safety of chemicals of synthetic and natural origin can

be obtained from the subacute toxicity studies, which

involve repeated administration of the chemical agent

under consideration. In subacute toxicity assessments,

weight loss of experimental animals is an important

variable that can be attributed to harmful eﬀects of test

substances [179]. A weight loss, that may be attributed

to the anti-nutritive and malabsorption eﬀect of chemi-

cal agents, that amount to ≥ 10% can be considered a

sign of toxicity even in the absence of other changes

on target organs, haematological or biochemical eﬀects

[226]. e subacute toxicity of plant-based materials

including crude extracts, solvent fractions, bio-oils,

essential oils, etc. was evaluated through repeated

administration a speciﬁc dose in diﬀerent animal mod-

els with the intention of assessing its accumulation in

the body with gradual eﬀects on tissues and organs

[188]. In this regard, Loha etal. [179] assessed the suba-

cute toxicity of HME leaf extract of Syzygium guineense

in rats at 500 and 1500mg/kg of body weight. Herein,

the rats were devoid of signiﬁcant change on behavior,

gross pathology, body weight, and hematological and

biochemical parameters, asserting the safety proﬁle of

the leaf extract at a repeated dose of 1500mg/kg. In

addition, subacute toxicity study was conducted on EO

obtained from Echinops kebericho tuber at the doses of

100, 200 and 400mg/kg [201]. e EO treated groups

did not experience signiﬁcant dose-dependent altera-

tions in body weight, clinical chemistry parameters and

relative organ weights. Deyno et al. [202] conﬁrmed

that Echinops kebericho decoction was well tolerated up

to the dose of 600mg/kg body weight as food consump-

tion, body weight, organ weight, hematology, clinical

chemistry, and histopathology did not show signiﬁcant

alterations between control and treatment groups.

Moreover, subacute toxicity studies conducted on the

diﬀerent extracts of antiepileptic or anticonvulsant MPs

such as Allium sativum (AQ bulb extract at 300mg/kg)

[190], Artemisia abyssinica (ET extract of the aerial part

at 3000mg/kg) [191], Artemisia afra (AQ leaf extract

at 1800mg/kg) [175], Asparagus africanus (HET and

BU root extracts) [182], Azadirachta indica (AQ leaf

extract at 1000 mg/kg) [176], Capparis tomentosa

(HME root extract at 1000 mg/kg) [184], Eucalyptus

Globulus (EO of leaf at 2mL/kg) [178], Olea europaea

(ET leaf extract at 400 mg/kg) [212], Opuntia ﬁcus-

indica (HET stem extract at 2000mg/kg) [213], Myrica

salicifolia (HME root extract at 400mg/kg) [211], Sida

rhombifolia (AQ root extract at 1200mg/kg) [221], and

Withania somnifera (ME root extract at 2000mg/kg)

[185] clearly asserted their safety proﬁles at the respec-

tive maximum doses per body weight as manifested

by the absence of signiﬁcant treatment related varia-

tions in clinical observations, ophthalmic examination,

body weight gain, feed consumption, clinical pathology

evaluation, organ weight, and so on. On the other hand,

notable discomforts or mild signs of toxicities were

observed on rats treated with some MPs utilized in the

management of epilepsy and related symptoms. For

instance, Zewdu et al. [203] conducted subacute tox-

icity study on the HET fruit extract of Embelia Schim-

peri in Wistar rats at doses of 400 and 1600mg/kg body

weight. e result revealed that chronic administration

of the extract (1600mg/kg) was not signiﬁcantly associ-

ated with body weight loss and organ weights such as

liver and kidney. Some haematological and biochemi-

cal parameters such as platelets and AST concentration

were signiﬁcantly increased which may be attributed to

inﬂammation of liver and kidney tissue upon repeated

dose exposure, stressing the mild toxicity of the fruit

extract of Embelia Schimperi at a dose of 1600mg/kg

or higher. In addition, ﬁxed oil of Zingiber oﬃcinale

root was found to have inherent propensity to trigger a

range of toxicities (0.4mL/kg) including hypertrophy of

the liver, kidneys, lungs and spleen, cellular toxicity and

oxidative stress following 60-day subchronic toxicity

study [224]. Similarly, repeated administration of Clero-

dendrum myricoides AQ root extracts in mice causes

reduction in body weight gain, damage to the liver and

kidney and changes in some hematological and bio-

chemical parameters in mice. e research group also

reported the signiﬁcant body weight loss of the AQ leaf

extract of Croton macrostachyus at 1000mg/kg in the

treated groups [227].

Page 26 of 37

Birhan Chinese Medicine (2022) 17:129

Developmental toxicity proles ofmedicinal plants

Prenatal development is comprised of pre-embryonic,

embryonic and fetal stages. e embryonic stage is a

critical period where organs of the embryo as well as

the placenta can be damaged if exposed to toxic agents

directly or indirectly. At times, toxic agents may cross the

compromised placental membrane and elicit debilitating

eﬀect on the developing embryonic/fetal tissues [228].

e developmental toxicity studies of crude extracts,

solvent fractions and/or essential oils has paramount

healthcare implications for PS consumed by pregnant

women for therapeutic as well as nutritional purpose

[229]. In this regard, the eﬀect of some MPs that are

frequently employed to relive seizure in patients with

epilepsy on prenatal growth (developing embryos and

fetuses) are assessed by using diﬀerent animal models.

For instance, the developmental eﬀect HET fruit extract

of Embelia schimperi on embryo and fetuses was inves-

tigated by using Wistar albino rats and the result ech-

oed that the crude extract was devoid of a signiﬁcant

toxic eﬀect on embryonic and fetal development indices

(in the period of organogenesis) at a dose of 1000 mg/

kg body weight [230]. Similarly, the HET leaf extract of

Syzygium guineense was evaluated at a dose of 250, 500

& 1000mg/kg in the same animal model and the extract

didn’t compromise the number of implantations, fetal

resorptions, live births, and stillbirths in the same ani-

mal model though there was dose-dependent decrease in

the weight of the fetuses and the placentae [228]. Abebe

etal., also assessed the teratogenic potentials of the HET

leaf extract of Gloriosa superba on Wistar albino rats

(220–240g) at a dose of 250, 500 and 1000mg/kg of body

weight. e crude extract was devoid of any signiﬁcant

teratogenic eﬀects on rat embryos/fetuses up to 500mg/

kg but inﬂuenced the growth of embryos at 1000mg/kg

of body weight as manifested by diminished crown-rump

length, decreased number of somites and morphological

scores [231]. Moreover, the teratogenic eﬀect of the HME

leaf extract of Catha edulis was investigated on pregnant

Wistar albino rats at a dose of 250, 500 & 750mg/kg of

body weight. e result echoed that khat extract pre-

sented dose-dependent toxicity in rat embryo and fetuses

such as cytolysis, decidual hypoplasia and atrophy [232].

Overall, the aforementioned acute, subacute and devel-

opmental toxicity results witnessed the safety of MPs

utilized in the management of epilepsy and related symp-

toms in Ethiopia.

Phytochemistry ofmedicinal plants

withanticonvulsant activities

MPs have been used as a source of pharmaceutical

agents for numerous indications and among small mol-

ecule drugs approved between 1981 and 2010, more

than half were derived from natural products, mainly

plants [233]. Cannabidiol is the ﬁrst AED of plant ori-

gin (extracted from Cannabis sativa) approved by the

United States Food and Drug Administration (FDA) in

2018 for the treatment of two rare and severe forms of

epilepsy, Dravet syndrome and Lennox-Gastaut syn-

drome [234]. In LMICs, MPs are consistently used for the

treatment of several CNS disorders including epilepsy

partly due to their tolerable side eﬀects and impressive

eﬃcacy [18]. Most of the MPs prescribed for epilepsy

treatment by THs have shown promising anticonvul-

sant activity against stimuli-induced invitro and invivo

seizure models [8, 146]. Generally, phytochemical con-

stituents of MPs which belong to the class of alkaloids,

ﬂavonoids, terpenoids, glycosides, coumarins, etc. are

implicated in the amelioration of convulsions as con-

ﬁrmed by diﬀerent animal models [235]. ey act on

diﬀerent targets such as synapses, receptors, and asso-

ciated neuronal pathways, ion channels, immune sys-

tem, inﬂammatory mediators, glial cells, etc. implicated

in the occurrence and progression of epileptogenesis

[235]. e antiepileptic activity of MPs discussed before

was mostly based on the crude extract or EO rather than

isolated active compounds. Consequently, it is diﬃcult

to gain full insight into the active constituents, possible

targets, eﬀective doses, and MOA of antiepileptic PMs.

is section highlights the phytochemical constituents

of MPs claimed by THs for their curative eﬀects against

epilepsy and proved by in vivo experiments using dif-

ferent stimuli-induced seizure models. It is noteworthy

to mention that the bioactive compounds or secondary

metabolites of MPs discussed below are obtained from

independent phytochemical screening or investigations

done elsewhere regardless of their use citations. In this

regard, several phytoconstituents with profound anticon-

vulsant activities were found in diﬀerent parts includ-

ing leaf, stem, stembark, root, rootbark, rhizome, ﬂower,

aerial and whole part, etc. of the reported antiepilep-

tic MPs (Table6). Flavonoids and terpenoids (including

monoterpenes, sesquiterpenes, diterpenes, triterpenes)

are the most frequently encountered phytochemicals in

the antiepileptic MPs discussed in previous sections.

Flavonoids withanticonvulsant activities

Flavonoids, often synthesized by the phenylpropanoid

pathway, belong to a class of phenolic compounds with

a benzo-γ-pyrone structure that is ubiquitously distrib-

uted in plants [265, 266]. ey are the ﬁrst class of phy-

tochemicals involved in the suppression of seizures in

diﬀerent animal models. Apigenin (Fig.2) is one of the

most common ﬂavones found in Ajuga integrifolia, Bal-

anites aegyptica, Nicotiana tabacum, and Olea europaea

among others. It elicited pronounced anticonvulsant

Page 27 of 37

Birhan Chinese Medicine (2022) 17:129

activity in PTC-induced seizures in SD rats as well as

KA-induced seizure model through activation of GABAA

receptor and inhibition of glutamatergic neurotransmis-

sion. Moreover, apigenin possesses inhibitory activity

against hydroxyl radical generation through upregulation

of reduced glutathione (GSH), consequently, can inhibit

neuronal damage in the hippocampal caused by oxida-

tive glutamate toxicity (involved in neuronal death due

to epilepsy) [267]. Rutin is a ﬂavonoid glycoside and a

constituent of Balanites aegyptica, Buddleja polystachya,

Carissa edulis, Opuntia ﬁcus-indica, Ruta chalepensis

among others with profound invivo antiepileptic activi-

ties. Rutin ameliorated PTZ-kindling in KA-induced

seizure upon intraperitoneal (IP) administration. It was

devoid of signiﬁcant anticonvulsant activity against PTZ

and MES-induced seizure models (at 800 mg/kg) when

administered through the IP route. However, intrac-

erebroventricular administration of rutin suppressed

clonic and GTCS in the PTZ-induced model. us, the

eﬀect on GABA, the glutamate pathway, acetylcholine,

glycine, serotonin, and adenosine receptors might be

implicated for the observed anticonvulsant activity of

rutin. Moreover, the antioxidant activity of rutin may

also play a crucial role in its antiepileptic outcome [268].

Quercetin is a ﬂavonoid found in Ajuga integrifolia,

Allium sativum, Balanites aegyptica, Nicotiana tabacum,

Olea europaea, Opuntia ﬁcus-indica, Ruta chalepen-

sis, and Xanthium stramonium that exhibited noticeable

anticonvulsant activities in diﬀerent seizure models. In

the KA-induced seizure model involving BALB/c mice,

quercetin recorded lower seizure scores as compared

to the negative control group [269]. It also elicited sig-

niﬁcant anticonvulsant outcomes after 30 and 60 min

of administration in psychomotor seizures induced by

6-Hz simulation. In addition, it also prolonged the onset

of seizures and reduced the generalized seizure duration

in PTZ-induced convulsions in the male Albino rat at a

dose of 10mg/kg. Furthermore, at 20mg/kg, quercetin

ampliﬁed the latency of PIC-induced seizures [6].

Terpenoids withanticonvulsant activities

Monoterpenes

Terpenoids, also known as terpenes or isoprenoids, are

naturally occurring compounds derived from isoprene

units and predominantly found in all classes of living

organisms [270]. Terpenoids are often classiﬁed based

on the number of carbon atoms or isoprene units (IPU)

they possess: monoterpenes (C10, 2 IPU), sesquiterpenes

(C15, 3 IPU), diterpenes (C20, 4 IPU), triterpenes (C30,

6 ITU), etc. [271]. Terpenoids in general and monoter-

penes speciﬁcally are used for the management of CNS

disorders including epilepsy. α-Terpineol is monoter-

pene alcohol obtained from Artemisia afra, Buddleja

polystachya, Croton macrostachyus, Ruta chalepensis,

and Zingiber oﬃcinale. It has shown signiﬁcant anti-

convulsant activity in PTZ and MES-induced seizure

models. Albeit, the exact seizure suppression mecha-

nism of α-terpineol is not known yet [268]. Menthol

is a monoterpene found in Ruta chalepensis shown to

have profound anticonvulsant eﬀects in diﬀerent animal

models. It elicited its antiseizure activity by delaying the

onset of clonic and tonic seizures against PTZ-induced

Table 6 Phytoconstituents of MPs with in vivo antiepileptic/anticonvulsant activities

No. Scientic name Active compounds Refs.

1Ajuga integrifolia Apigenin and quercetin [236]

2Allium sativum Quercetin [237]

3Artemisia afra Borneol, camphor, eucalyptol, eugenol, p-cymene, phytol, α-terpineol, and β-caryophyllene [238, 239]

4Azadirachta indica Phytol [240]

5Balanites aegyptica Apigenin, quercetin and rutin [241]

6Buddleja polystachya Camphor, phytol, rutin, ursolic acid and α-terpineol [242–244]

7Carissa edulis Lupeol and rutin [245, 246]

8Croton macrostachyus Lupeol, linalool, p-cymene, α-terpineol, and β-caryophyllene [247–249]

9Jatropha curcas Lupeol, phytol and rutin [250–252]

10 Maytenus heterophylla Lupeol [253]

11 Nicotiana tabacum Apigenin, lupeol and quercetin [254, 255]

12 Olea europaea Apigenin, oleuropein and quercetin [256]

13 Opuntia ﬁcus-indica Quercetin and rutin [257]

14 Ruta chalepensis Borneol, camphor, carvacrol, linalool, menthol, pulegone, quercetin, rutin and α-terpineol [258–260]

15 Sida rhombifolia Lupeol [261]

16 Xanthium stramonium Borneol, lupeol, p-cymene, quercetin, β-caryophyllene [262, 263]

17 Zingiber oﬃcinale 6-gingerol, borneol, camphor, citral, citronellol, linalool, p-cymene, α-terpineol and β-caryophyllene [168, 264]

Page 28 of 37

Birhan Chinese Medicine (2022) 17:129

convulsions. Moreover, it also suppressed seizures in hip-

pocampal kindled rats. GABAA receptor activation in

the hippocampal neurons and thereby inhibition of neu-

ronal excitation (tonic GABAergic inhibition) is believed

for the beneﬁciary eﬀect of menthol against epileptiform

[170]. Camphor is monoterpene predominantly found in

PMs such as Artemisia afra, Buddleja polystachya, Ruta

chalepensis, and Zingiber oﬃcinale among others showed

signiﬁcant anticonvulsant activity in diﬀerent models.

Moreover, it served as a pharmacophore for the syn-

thesis of diﬀerent anticonvulsant agents. In this regard,

benzylidene camphor derivatives containing hydrazone,

semicarbazones and thiosemicarbazones exhibited sig-

niﬁcant antiepileptic activity against MES-induced sei-

zures at 30mg/kg (comparable to phenytoin) with low

neurotoxicity [272]. p-cymene is a constituent of Artemi-

sia afra, Croton macrostachyus, Xanthium stramonium

and Zingiber oﬃcinale possess anticonvulsant activities.

It suppressed convulsions induced by PTZ and MES in

mice through modulation of GABAergic neurotransmis-

sion via GABAA receptor [273, 274]. Citral is another

monoterpene found in Zingiber oﬃcinale with biological

importance for the treatment of CNS malfunction such

as epilepsy. It increased the latency time in PTZ-induced

seizure in zebraﬁsh larvae model. Its eﬀect is compro-

mised in ﬂumazenil (FMZ) pretreated groups suggesting

the contribution of GABAA receptors. Moreover, down-

regulation of malondialdehyde (MDA)/NO and upregu-

lation of reduced GSH/catalase (CAT) in brain of citral

treated groups reiterated its neuroprotective eﬀect [275].

Fig. 2 Bioactive compounds isolated from plants with anticonvulsant/antiepileptic and convulsive activities

Page 29 of 37

Birhan Chinese Medicine (2022) 17:129

Pulegone is another monoterpene found in Ruta cha-

lepensis that signiﬁcantly increased the latency of convul-

sions in PTZ-induced seizure models [276]. Oleuropein

is a glycosylated Seco-iridoids that can be predominantly

found in Olea europaea [256]. It unveiled substantial

anticonvulsant activity against PTZ-induced seizure

through avoidance of neuronal damage via attenuation

of generation of reactive oxygen species (ROS) in the epi-

leptic brain [161].

Sesquiterpenes andditerpenes

Sesquiterpenes are the other class of terpenoids with

potential anticonvulsant activities. β-caryophyllene is

a natural sesquiterpene obtained from Artemisia afra,

Croton macrostachyus, Xanthium stramonium, and Zin-

giber oﬃcinale. Contrary to its outcome in PTZ-induced

convulsions, β-caryophyllene has reduced seizure sever-

ity and OS in the KA-induced seizure model. e result

revealed the potential of β-caryophyllene to suppress

seizure by inhibiting thiobarbituric acid reactive species

and elevating non-protein thiol levels in the KA model

[277]. Diterpenes and their derivatives are among the

single compounds that demonstrated relevant antisei-

zure activities in animal models. Phytol is a component

of Artemisia afra, Buddleja polystachya, Jatropha cur-

cas, etc. It reduced SE and PLC-induced convulsions

by targeting neurotransmitters other than the GABAe-

rgic system [268]. 6-GIN, major constituent of Zingiber

oﬃcinale rhizome, is a diterpenoid with potent anticon-

vulsant activity. It exerted dose-dependent antiepileptic

activity against PTZ-induced hyperlocomotion seizure

in the zebraﬁsh larvae model. Its anticonvulsant activity

is partly associated with the restoration balance between

GABA & GLU neurotransmission in the epileptic brain

[168].

Triterpenes

Triterpenoids are a diverse class of phytochemicals

with potential CNS eﬀects such as memory enhance-

ment, ameliorating of depression, suppression of epi-

lepsy, etc. Borneol is a triterpenoid found in Artemisia

afra, Ruta chalepnesis, Xanthium stramonium, and

Zingiber oﬃcinale with the ability to alleviate ES in dif-

ferent animal models. It produced an enhanced time of

onset of clonic seizures in PTZ-kindled mice. Moreover,

the PTZ-kindling was counteracted by borneol as mani-

fested by the decrease in lipid peroxidation (LPO) levels,

increased superoxide dismutase (SOD), GSH, CAT levels

[278]. Carvacrol, a triterpenoid found in Ruta chalep-

nesis, suppressed the onset of clonic seizure in the same

model at relatively higher doses. ese phytoconstitu-

ents showed antiepileptic activities after deactivation of

GABAA receptor by FMZ, suggesting the involvement

of GABAergic neurotransmission in containing seizures

through indirect activation of BZP site of GABAA-BZP

receptors [279]. Citronellol is also another class of trit-

erpenoid found in diﬀerent MPs including Zingiber

oﬃcinale. Inhibition of neuronal excitability through

voltage-dependent Na+ channels is the proposed mecha-

nism for the antiepileptic activity of citronellol. Moreo-

ver, it also activates the GABAA receptor and thereby

foster GABA neurotransmission in the rat brain [280].

Eugenol is a triterpenoid obtained from Artemisia afra.

At 100mg/kg, eugenol suppressed SE and related mor-

tality in PLC-induced SD rats. e involvement of

voltage-gated Na+ channel in the anticonvulsant activ-

ity of eugenol was proved by its weakened eﬀect upon

pre-administration of the Na+ channel antagonist, rilu-

zole [281]. Linalool is found in Croton macrostachyus,

Ruta chalepensis and Zingiber oﬃcinale. It suppressed

quinolic acid (QA)-induced seizure (via NMDA antago-

nism), delayed NMDA-induced convulsions, increase

latency onset and duration of clonic seizures in the PTZ-

kindling model. e later seizure model also proved the

involvement of a wide array of mechanisms despite glu-

tamate blockage [268]. Ursolic acid is a pentacyclic trit-

erpenoid obtained found in Buddleja polystachya. It has

a profound anticonvulsant activity possibly by modulat-

ing the non-BZP sites of the GABAA receptor. In addi-

tion, it also showed an anticonvulsant eﬀect in MES- and

6Hz-induced seizure models through activation of the

GABAergic pathway [282]. Lupeol is a triterpenoid found

in Carissa edulis, Croton macrostachyus, Jatropha cur-

cas, Maytenus heterophylla, Nicotiana tabacum, Sida

rhombifolia, Xanthium stramonium, etc. It has shown

anticonvulsant activities against PTZ and MES-induced

seizure models. Lupeol has increased the mean onset of

myoclonic jerks/spasms and diﬀerentially protected the

mice against mortality [172].

Proconvulsive phytoconstituents ofmedicinal plants

At this point, it is worthy to mention that some phyto-

constituents have convulsive activity (vigorous jerking of

the body and loss of consciousness). Crude extracts or

essential oils of some MPs can induce seizure upon sys-

temic or topical administration. Phytoconstituents such

as eucalyptol and camphor have shown a signiﬁcant con-

vulsive eﬀect [283]. For instance, one teaspoon of cam-

phor oil taken orally (by a 3year child) induced GTCS

and respiratory depression within 20min. On the other

hand, eucalyptol induced convulsions characterized by

the development of long-term SE and showed develop-

mental delay for at least four years following the event

[284]. us, attention should be given to antiepileptic

MPs which contain camphor (Artemisia afra, Buddleja

polystachya, Ruta chalepensis, and Zingiber oﬃcinale)

Page 30 of 37

Birhan Chinese Medicine (2022) 17:129

and eucalyptol (Artemisia afra) when used by THs to

manage the convulsive eﬀect and long-term side-eﬀects.

Extensive research could be conducted to determine the

tolerable dose which can delimit the protective and con-

vulsive outcomes of camphor and eucalyptol. Overall, the

anticonvulsant activities of phytoconstituents included in

Table5 signiﬁes the therapeutic potential of the antiepi-

leptic MPs and the importance of evidence-based phyto-

chemical screening to maximize the beneﬁt of MPs and

bring about new AEDs of plant origin.

Conclusion

Plants have a central role in the traditional medicinal

folklore of Ethiopia. Around 96 PS which belong to 43

families were reported for the treatment of epilepsy and

related symptoms in diﬀerent parts of Ethiopia. A por-

tion of these PS was also used for the same purpose in

Africa, the Middle East, Asia, and Latin America. e

pharmacological activities of nearly one-third of the MPs

claimed by the THs for attenuation of seizure in Ethio-

pia and other parts of the globe were veriﬁed by invivo

experiments using diﬀerent animal and seizure mod-

els. e experimentally proved anticonvulsant activities

of MPs have presented the importance of indigenous

knowledge and the existing traditional healthcare sys-

tem in the management of epilepsy in diﬀerent coun-

tries, especially in Ethiopia. A strong association between

traditional herbal formulations and pharmacological

activities of antiepileptic MPs has been established. Yet,

the vast majority of the MPs documented in the present

review were not screened for their anticonvulsant activi-

ties. In addition, the invivo experiments conducted else-

where on the target MPs are shallow and not insightful as

far as the MOA of crude extracts, solvent fractions, and

EOs are concerned. Furthermore, the invivo pharmaco-

logical experiments (anticonvulsant activities) were not

accompanied by isolation and characterization of bioac-

tive phytoconstituents responsible for the antiepileptic

MPs. Overall, the majority of the PS documented in this

review require additional investigation on pharmacologi-

cal activities, potential targets and mechanism of seizure

attenuation, isolation and characterization of bioactive

compounds, and toxicological analysis to validate the sig-

niﬁcance of MPs to tackle epilepsy-associated comorbidi-

ties and mortalities.

Abbreviations

AMP: Aminophylline; AEDs: Antiepileptic drugs; AEMNAs: Antiepileptic medi-

cations non-adherences; AQ: Aqueous; BIC: Bicuculline; BU: Butanol; CAT : Cata-

lase; CNS: Central nervous system; CH: Chloroform; CAMs: Complementary and

alternative medicines; ET: Ethanolic; ES: Epileptic seizures; FMZ: Flumazenil;

GTCS: Generalized tonic clonic seizures; GLU: Glutamine; GSK-3: Glycogen syn-

thase kinase-3; HET: Hydroalcoholic/hydroethanolic; HME: Hydromethanolic;

IP: Intraperitoneal; INH: Isonicotinic hydrazide acid; IPU: Isoprene units; KA:

Kainic acid; LPO: Lipid peroxidation; LMICs: Low- and middle-income coun-

tries; MDA: Malondialdehyde; MES: Maximal electroshock; MOA: Mechanism

of action; MPs: Medicinal plants; ME: Methanolic; NCAM: National center for

complementary and alternative medicines; NMDA: N-methyl-D-aspartate;

OS: Oxidative stress; PE: Petroleum ether; PIC: Picrotoxin; PLC: Pilocarpine; PS:

Plant species; PTZ: Pentylenetetrazol; QOL: Quality of life; QA: Quinolic acid;

ROS: Reactive oxygen species; GSH: Reduced glutathione; SNNP: Southern

nations nationalities and peoples; SE: Status epilepticus; STR: Strychnine; SOD:

Superoxide dismutase; THS: Traditional healers; FDA: United States Food and

Drug Administration; TM: Traditional medicine; VPA: Valproic acid; WHO: World

Health Organization and GABA, γ-aminobutyric acid.

Acknowledgements

The author would like to acknowledge Mr. Enawgaw Acham Jemberu for

drawing the location map of Ethiopia.

Authors’ contributions

YSB collected the relevant works of literature and compiled the review.

Funding

The review did not receive any speciﬁc grant from funding agencies.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The author declares that there are no competing interests.

Received: 4 October 2022 Accepted: 7 November 2022

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Elemental Profile of Selected Plant Species used for the Treatment of Epilepsy in Idah Local Government

Article

Nov 2024

Epilepsy is a disorder in the brain, in which clusters of nerve cells, or neurons, occasionally signal abnormally and cause strange emotions, sensations, and behaviour, or sometimes muscle spasms, convulsions, and loss of consciousness. The study was conducted to identify the effect of medicinal plants used for the treatment of epilepsy in Idah LGA of Kogi State. To determine the mode of treatment, their mode of treatments, plant parts used for treatments, and the appropriate dosage, as well as to analyze the phytochemical constituents of the plants and the demographic status of the respondents indicated that Twenty (20) herbal practitioners were interviewed. The male respondents were 13 while the women were 7. The disease was more prevalent among the males than in females in the study area, only a few of the respondents (3) acquired tertiary education. Most of the respondents (15) were rural residents. Majority of the respondents (10) were Muslims, while only 2 were Christians. Four (4) plants (Ocimum gratissimum, Solanum physalifolium, Asplenium scolopendrium and Spathodea companulata) were identified. Only the leaves of the plants were used for the treatment of epilepsy. The best mode of treatment was established to be boiling and compressing to extract the liquid (juice) from the leaves across the plant tested. The phytochemical constituents of the plants studied revealed the presence of alkaloids recorded the highest phytochemical constituents (9.250), followed by saponin (2.370) while tannins recorded the lowest (0.528). It can be concluded that Idah LGA has a diverse plant species with antiepileptic properties that could be used holistically for the treatment of several diseases, notably epilepsy. The various methods of administration of these plants for possible treatment of epilepsy will be discussed.

Phytochemical, Antioxidant, Anti-Nociceptive and Anti-Inflammatory Studies of the Water and Methanol Extracts Obtained from the Leaves of Fagaropsis Angolensis (Engl.) H.M. Gardner (Rutaceae)

Article

Aug 2024

Fagaropsis angolensis is widely used in African traditional medicine system to manage oxidative stress-associated diseases and lacks scientific evidence. The study investigated the phytochemical, antioxidant, anti-nociceptive and anti-inflammatory properties of F. angolensis leaf extracts. Extracts were prepared by maceration and standard qualitative methods were used for phytochemical screening. Total phenolic and total flavonoid contents were done by using Folin-Ciocalteu and aluminum chloride calorimetricmethods, respectively. Antioxidant activity was evaluated using 2, 2-Diphenyl-1- picrylhydrazyl (DPPH) method. Acetic acid-induced writhing and carrageenan-induced hind paw edema mouse models were used in anti-nociceptive and anti- inflammatory activities respectively. The presence of steroids, phenols, alkaloids, flavonoids, anthraquinones, glycoside and coumarins were observed. Total phenolic content for methanol extract was 55.52 ± 3.05 and the water extract was 48 ± 0.185 mgGAE/g (p<0.05). While, total flavonoid content for methanol extract was 172.53 ± 7.095 and that of water extracts was 42.23 ± 0.101 mgCE/g (p<0.05). IC50 values of less than 1 μg/ml were revealed in the DPPH assay. Percentage (%) writhing inhibition did not show any difference between the tested doses of plant extracts and standard aspirin at 150 mg/kg (p>0.05), indicative of potent anti-nociceptive activity. There was no significant difference in percentage paw edema inhibition between the plant extracts and the dexamethasone standard at 10 mg/kg (p>0.05), indicative of potent anti-inflammatory activity.This study adds to existing knowledge about the utilization of F. angolensis in traditional medicine for the management of related to oxidative stress including pain and inflammatory reactions.

Unlocking the Folkloric Uses of Rhus retinorrhoea Steud. Ex A. Rich Leaf Crude Extracts: Phytochemical Screening, Antioxidant and Antibacterial Activities

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Mar 2025

Euphorbia serpens Extracts Mediated Synthesis of Copper oxide Nanoparticles and their Biological Applications

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Dec 2024

Conceptual framework to provide culturally congruent care to epilepsy patients in selected rural communities in South Africa

Article

Full-text available

Dec 2024

Background Epilepsy is a neurological disorder affecting millions of people in Africa. Among other reported findings, many people living with epilepsy (PLWE) believe that the condition is caused by spiritual factors. Previous studies have revealed that majority of PLWE are not receiving adequate care and treatment because of diverse cultural beliefs associated with epilepsy. Consequently, they consult either faith-based healers or traditional healers. Others, however, acknowledge the medical causes of epilepsy and seek developed medical treatment. Aim To develop a culturally congruent care conceptual framework to provide comprehensive and holistic epilepsy care. Setting This study was conducted in the selected rural communities of Limpopo and Mpumalanga provinces. Methods A qualitative multi-method research approach was employed and sub-divided into three phases. Phase 1: All 15 articles were reviewed and appraised using the Critical Appraisal Skills Programme (CASP) rating tool. Phase 2 involved two stages of empirical study in which an exploratory-descriptive study design was used. The study population comprised of 20 traditional healers, 15 faith-based healers, 20 professional nurses and 22 PLWE. Data were collected using in-depth individual interviews and analysed through eight Tesch’s steps of data analysis. Following data analysis, Phase 3 entailed synthesising the systematic and empirical findings into a conceptual framework. Results Three themes that emerged from the findings were cultural epilepsy interventions, faith-based epilepsy intervention and medically developed epilepsy interventions. Conclusion Incorporation of cultural beliefs, values and practices into the medically developed management of epilepsy is crucial for providing culturally congruent care that is preferred by majority of PLWE. Contribution Healthcare providers may tailor care interventions that are culturally appropriate and acceptable hence promoting early diagnosis and treatment adherence leading to improved quality of life.

Ethnoveterinary Practices for Wild Medicinal Plants from Malawi, Rwanda, and Ethiopia: A Critical Review

Article

Full-text available

Dec 2024

Ethnoveterinary practices, particularly the use of wild medicinal plants, play a significant role in animal healthcare in many rural communities of Malawi, Rwanda, and Ethiopia. These traditional practices provide affordable and culturally relevant alternatives to conventional veterinary medicine, especially where access to modern animal healthcare is limited. However, despite their potential, limited documentation and systematic evaluation of these practices pose challenges for their integration into broader animal health strategies and conservation efforts. This critical review aims to synthesize available knowledge on wild medicinal plants used in ethnoveterinary medicine across the three countries, focusing on plant species, preparation methods, dosage, and efficacy. The methodology involved a comprehensive literature search of peer-reviewed articles using databases such as PubMed, Scopus, and Web of Science. Inclusion criteria were applied to identify studies documenting traditional uses, plant preparation, dosage, and efficacy. Data extraction focused on key plant species, ethnoveterinary applications, preparation techniques, and reported effectiveness. Findings reveal a diverse range of wild plants utilized for treating various animal health issues, such as gastrointestinal disorders, wounds, and parasitic infections. Preparation methods often include decoctions, infusions, and topical applications. While many plants are reputed to have high efficacy, scientific validation remains limited for many species. The review underscores the need for further pharmacological studies and policy measures to protect traditional knowledge and biodiversity. This study highlights the critical role of ethnoveterinary practices in enhancing animal health and emphasizes the need to integrate traditional and modern approaches, promoting conservation and sustainable utilization of wild medicinal plant resources.

Análise prospectiva do potencial antiepiléptico de espécies das famílias Passifloraceae, Zingiberaceae e Cannabaceae

Article

Full-text available

Jul 2024

A epilepsia é uma condição neurológica crônica caracterizada por convulsões recorrentes e sem cura definitiva, afetando significativamente a qualidade de vida dos pacientes. O tratamento convencional envolve o uso de drogas antiepilépticas, que, embora sejam eficazes no controle das crises, podem causar uma série de efeitos colaterais prejudiciais e não abordam a causa subjacente da doença. Além disso, pacientes com epilepsia resistente a medicamentos enfrentam desafios adicionais, incluindo comprometimento cognitivo e baixo desempenho educacional e ocupacional. Nesse contexto, a pesquisa de novas alternativas de tratamento para a epilepsia se torna crucial. Uma área promissora é o estudo dos extratos naturais de plantas medicinais, que têm sido investigados por seu potencial antiepilético. Este estudo se concentra nas famílias Passifloraceae, Zingiberaceae e Cannabaceae devido à sua riqueza em compostos bioativos com propriedades farmacológicas. A pesquisa científica revelou que várias espécies dessas famílias de plantas possuem atividades antiepilépticas e anticonvulsivantes, fornecendo uma base para o desenvolvimento de novos tratamentos. No entanto, os desafios enfrentados na obtenção de patentes e no desenvolvimento de produtos fitoterápicos no Brasil destacam a necessidade de investimentos adicionais e políticas regulatórias claras nessa área. Portanto, a pesquisa contínua sobre o potencial terapêutico das plantas medicinais, juntamente com esforços para melhorar o acesso a tratamentos inovadores, é essencial para melhorar o manejo da epilepsia e a qualidade de vida dos pacientes.

Pharmacological Analysis of Natural Products and medicinal Plants with Anti-epileptic Properties Journal of Cardiovascular Disease Research

Article

Full-text available

May 2024
J Cardiovasc Dis Res

Epilepsy is a neurological disorder that presents with recurring and spontaneous seizures. It is prevalent worldwide, affecting up to 65 million people, with 80% of cases found in lower-income countries. Medicinal plants are commonly employed for managing and treating epilepsy and convulsions due to their unique therapeutic properties. With increasing research and clinical application, medicinal plants are gaining attention globally due to their potent therapeutic effects and fewer side effects. The development of new plant-based antiepileptic/anticonvulsant agents has become a major focus in the pharmaceutical industry. This article summarizes recent research on medicinal plants with reported antiepileptic/anticonvulsant effects. It provides pharmacological and molecular mechanism of action information for the crude extracts and related active constituents evaluated in preclinical research for the treatment of epilepsy and convulsions, and offers a reference for the development of future related studies in this area. Articles related to ethnopharmacological and antiepileptic studies on plants or natural products from recent and most recent were collected from PubMed, Web of Science and Scopus, etc. using keywords related to epilepsy, medicinal plants, and natural products, etc. Different plant species are commonly used to treat epilepsy and convulsions in African and Asian countries. Also, natural products showing potential for antiepileptic/anticonvulsant effects have been identified from these medicinal plants. These products can be broadly classified as alkaloids, coumarins, flavonoids, saponins, terpenoids and other compounds. The antiepileptic action of plant extracts and their active ingredients can be classified according to their abilities to modulate the GABAergic and glutamatergic systems, act as antioxidants, exhibit anti-neuroinflammatory effects, and provide neuroprotection. In addition, we highlight that some medicinal plants capable of pharmacologically relieving epilepsy and cognition may be therapeutically useful in the treatment of refractory epilepsy. The review highlights the fact that herbal medicinal products used in traditional medicine are a valuable source of potential candidates for antiepileptic drugs. This confirms and encourages the antiepileptic/anticonvulsant activity of certain medicinal plants, which could serve as inspiration for further development. However, the aspects of structural modification and optimization, metabolism, toxicology, mechanisms, and clinical trials are not fully understood and need to be further explored.

The Anti-Convulsant Effects of Carvacrol in Penicillin- and Pentylenetetrazole-Induced Rat Models of Epilepsy

Article

May 2024

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

Article

Full-text available

May 2024

Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

EVALUATION OF ANTIEPILEPTIC ACTIVITY OF ETHANOLIC EXTRACT OF POPULUS DELTOIDES LEAF IN MICE

Article

Full-text available

Jan 2018

Populus deltoides leaf commonly known as eastern cottonwood belongs to the Salicaceae family. In the present study, Ethanolic extract of Populus deltoides leaf (EEPL) was tested for anticonvulsant activity in albino mice, using different convulsive models. The Ethanolic extract of Populus deltoides leaf produced significant anticonvulsant activity in all models studied. The present study also revealed that EEPL increase the concentration of nor-adrenaline and dopamine in brain of mice which attributed to the significant protection against MES induced seizures. Significant results were observed in the estimated parameters thereby justifying the use of this medicinal plant in the treatment of epilepsy.

Ethnobotanical study of medicinal plants in Kolli hills

Article

Full-text available

Jul 2022

Teratogenic Evaluation of 80% Ethanol Extract of Embelia schimperi Vatke Fruits on Rat Embryo and Fetuses

Article

Full-text available

Oct 2022

Introduction: Embelia schimperi Vatke (family Myrsinaceae) is a commonly consumed anthelminthic plant in Ethiopia. The plant has significant efficacy in treating intestinal worms. However, there are limited data about the safety/toxicity of the plant. Moreover, the teratogenic effect of the plant is not yet well studied despite significant number of Ethiopian mothers consuming herbal medication during their pregnancy. Purpose: This study aimed to evaluate the teratogenic effect of the hydroalcoholic extract of E. schimperi fruit on rat embryos and fetuses. Methods: Pregnant albino Wistar rats were treated with 80% hydroalcoholic fruit extract of E. schimperi at 250 mg/kg, 500 mg/kg, and 1000 mg/kg dosage, whilst the controls were pair-fed and ad libitum groups. Maternal food intake, maternal weight gain, number of implantations, number of prior resorptions, fetal viability, fetal weight, fetal and embryonic crown-ramp length, placental weight, placental gross morphology and histopathology of placental tissue, number of somites, embryonic system, gross/visceral morphological malformations, and ossification centers were evaluated as teratogenicity indices. Results: The crude extract of E. schimperi did not exhibit a significant difference in most developmental indices including the development of a circulatory system, nervous system, and musculoskeletal systems among treated animals and the controls. However, histopathological evaluation of placentas from the treatment groups showed that inflammatory reactions and calcifications compared to the pair-fed and ad libitum controls. Conclusion: Administration of the 80% hydroalcoholic extract of E. schimperi fruit during the period of organogenesis in rats did not show a significant toxic effect on embryonic and fetal developmental indices. However, it might affect the structural integrity of the placenta as it is evidenced by inflammatory reactions and calcifications of decidua basalis of rat placenta.

Anticonvulsant Activity of Hydro Alcoholic Extract and Solvent Fractions of Biophytum umbraculum Welw. Syn (Oxalidaceae) Root in Mice

Article

Full-text available

Oct 2022

Background Scientists and researchers continue to focus on medicinal plants as a potential source of lead chemicals in the search for and development of new antiepileptic medicines. Biophytum umbraculum Welw. Syn is used to treat epilepsy in Ethiopian traditional medicine. The anticonvulsant effect of Biophytum umbraculum Welw. Syn hydroalcoholic extract and solvent fractions was evaluated in this study since the claim has not been thoroughly explored. Methods The plant’s root was extracted using the maceration procedure, with aqueous, butanol, and chloroform as solvents. The maximum electroshock and pentylenetetrazol model tests were used to assess anticonvulsant activity. Mice were divided into five groups (n = 6) at random. The test groups received 100, 200, and 400 mg/kg of hydroalcoholic extract and solvent fraction, respectively. For the maximum electric shock test, the positive control groups received 25 mg/kg phenytoin and 200 mg/kg valproate for the pentylenetetrazol test. The negative control was given 10 mL/kg of pure water or 2% Tween 80. Results There were no signs of toxicity in the hydroalcoholic extract or solvent extraction. When compared to the negative control, the hydro-alcoholic extract had a significant anticonvulsant effect in both the maximum electric shock test and the pentylenetetrazol test. In both cases, the butanol component had a comparable impact. In the pentylenetetrazol test, the chloroform fraction had a significant anticonvulsant effect when compared to the control at dosages of MB200 and MB400. Flavonoids, phenols, tannins, steroids, terpenoids, and saponins were found in both the hydroalcoholic and solvent fractions of the plant extract. Conclusion The plant appears to have promising anticonvulsant properties, and it might be used to generate novel anti-epileptic drugs, according to this study.

Prenatal Developmental Toxicity and Histopathological Changes of the Placenta Induced by Syzygium guineense Leaf Extract in Rats

Article

Full-text available

Oct 2022

Many of the traditional herbal products are served to the consumer without proper efficacy and safety investigations. A laboratory-based experimental study was employed to investigate the toxic effects of Syzygium guineense leaf extract on the fetal development and histopathology of the placenta in rats. Fifty pregnant Wistar albino rats were randomly allocated into five groups, each consisting of 10 rats. S. guineense leaf extract, at doses of 250, 500, and 1000 mg/kg of body weight, was respectively administered to groups I-III rats. Groups four and five were control and ad libitum control, respectively. The number of resorptions, implantation sites, and live or dead fetuses was counted. The weight and crown-rump length of the fetuses were measured. The histopathological investigation of the placenta was conducted. Administration of 70% ethanol extract of S. guineense leaves reduced weight gain and food intake of pregnant rats at p value <0.05. The crown-rump length of the near-term rat fetus was significantly reduced in rats treated with 1000 mg/kg body weight of S. guineense extract (p value <0.05). The plant extract did not affect the number of implantations, fetal resorptions, live births, and stillbirths. The weight of the fetuses and the placentae also decreased dose-dependently. Decidual cystic degeneration was the most prevalent histopathological change observed in a rat’s placenta treated with 1000 mg/kg body weight of S. guineense extract. Consumption of S. guineense leaves, especially at a high dose, may affect fetal development. Therefore, liberal use of S. guineense leaves during pregnancy should be avoided.

Traditional zootherapeutic prescriptions employed in the management of neurological and related disorders in Ethiopia

Article

Full-text available

Sep 2022

Yihenew S. Birhan

Biological form of Complementary and Alternative Medicines (CAMs) have been often practiced in the traditional healthcare systems (THS) worldwide. In this regard, medicinal animals (MAs), secretions, excreta and animal products (APs) are routinely employed in the preparation of traditional medicines (TMs) for the amelioration of different disorders globally, including Ethiopia. Recent reports echoed that different animal-based medicines (ABMs) are used for the treatment of neurological and related disorders (NRDs) such as epilepsy, evil spirit, evil eye, mental illness, mental disorder, tremor, nightmare, phobia, anxiety, migraine, etc. in different Regional states of Ethiopia. The present review documented around 42 MA species which belong to the class of mammals, reptiles, fishes, arthropods and birds where the former accounted for 66.67% of AS. Meat (15.85%) was the most frequently sought body part for remedy preparation followed by skin (14.63%) and bone (10.98%). The ABMs were administered for patients mainly through the oral (33.33%) and nasal (29.49) routes. Different traditional healthcare practitioners (THPs) reported the use of two or more animal species (AS) body parts and a combination of animal parts with medicinal plants (MPs) for the formulation of TMs to benefit from the synergistic effect of bioactivities of compounds present in the target animal parts and MPs. Although ABMs are priceless in the THS of Ethiopia, their sustainable is hampered by fear of zoonosis, habitat encroachment due to anthropogenic factors and poor conservation practices in the country. Thus, the-state-of-art zoonotic diseases (ZDs) surveillance system and a legal framework to curb destruction of wildlife habitats and hunting should be implemented to maximize the benefit of zootherapy in Ethiopia.

Ethnobotanical investigation of medicinal plants in Buska Mountain range, Hamar district, Southwestern Ethiopia

Article

Full-text available

Sep 2022

Background Despite the fact that ethnobotanical studies have been conducted in various parts of Ethiopia, compared with the existence of the multitude and diverse ethnic groups and their associated traditional knowledge, the studies are not comprehensive enough for all the localities and communities in the country. This is also true for the Hamar community of Southwestern Ethiopia, who are totally dependent on plants and plant products for their livelihood. Hence, this investigation was done to identify and record medicine plants and the native wisdom of the community in the area. Methods Three hundred twenty six (326) informants were selected from the 12 lowest governmental units (Kebeles) applying Cochran’s formula through stratified random sampling technique. From the total informants, 74 (48 males and 26 females) were purposively selected for in-depth discussion. Semi-structured interviews, focus group discussions, guided field walks as well as market surveys were used for data collection. Standard ethnobotanical analytical tools comprising ranking and comparison were used for the analysis. Preference ranking, pair-wise comparison, informant consensus factor, direct matrix ranking, Cultural Significance Index (CSI) and Jaccard’s similarity coefficient (JCS) as well as Analysis of Variances (ANOVA), applying SPSS (version 20) were computed. Results A total of 145 species practical to cure about 72 ailments of livestock and humans were recorded. Families Fabaceae (with 22% of species), Asteraceae (11%), and Lamiaceae (9%) were discovered as the most dominant families in the area. Shrubs contributed the most (40%) to the growth forms followed by herbs (26.5%). Fresh leaves of the plants were parts that are used most frequently in the area. The highest ICF value (0.94) was recorded for reproductive problem categories. There was a relatively very high dependence of the community on plants and plant products together with a hoarded indigenous knowledge in the area that positively correlated with age (r = 0.82). Conclusion The study's findings revealed that Buska Mountain range is a home for highly diverse and most dependable plant species and associated indigenous knowledge. However, because of the realized environmental threats in the area, the conservation efforts of the community should be invigorated and supported in order to sustain the biodiversity in general and the medicinal plant species in particular.

In vivo antimalarial activity, toxicity, and phytochemical composition of total extracts from securidaca longepedunculata Fresen. (polygalaceae)

Article

Jan 2019

JosephMwanzia Nguta

Effect of Acute and Chronic Treatment of the 80% Ethanolic Fruit Extract of Embelia schimperi on Blood, Liver and Kidney of Rats

Article

Jul 2017

Chemical Analysis and Medicinal Activities of Volatile Components from the Seeds of Croton Macrostachyus Plant

Article

Jan 2018

One of the Croton species that is known for its medicinal use is Croton macrostachyus (Euphorbiaceae). It is one of the eight Croton species found in Ethiopia. The wide range medicinal uses of Croton macrostachyus led scientists to isolate compounds from its different parts. The primary objective of this research study was therefore to characterize the constituents of seeds of Croton macrostachyus (Euphorbiaceae) plant using GC-MS and to analyse the antimicrobial (medicinal) activity of the seed oil. 75 g of the powdered seeds of Croton macrostachyus was used for the extraction of the essential oil using hydrodistilation method. The oil was characterized using GC-MS and its biological activity was tested against some bacteria by Disk-diffusion method. GC-MS analysis of essential oils of Croton macrostachyus has shown over 40 components. From these, 19 compounds for each origin representing 82.86 % of Croton macrostachyus oil were identified as major components of the essential oil. 4-Hexen-1-ol, (E), Bis(2-ethylhexyl) phthalate, [1,1'-Biphenyl]-2-acetic acid, Epizonarene, Cyclopentene, 3-isopropenyl-5,5-dimethyl and 3-Carene were some of the major compounds identified from the oil. Antimicrobial results also showed that the essential oil was effective to control the growth of bacteria. So, collaborative works should be done between chemists, microbiologists and medical professionals to develop better medicinal drugs for the treatment of bacterial, fungal and viral infections.

Medicinal plants utilized in the management of epilepsy in Ethiopia: ethnobotany, pharmacology and phytochemistry

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