The rapeutic impact of alkaloids in neurological diseases: A promising key molecule

Abstract

Neurological disease is a disorder of the nervous system. It may be associated with the central nervous system or peripheral nervous system. Neurological problems are disorders of specific neurons or loss of neurons with their structural or functional impairment. The specific reason for neurological diseases may be genetic defects, congenital disorders, infections, and environmental health issues. No doubt, there are various well-known synthetic medications are available for the treatment of neurological disorders but they exert many toxicities and ADRs (Adverse Drug Reactions). The identification of compelling and promising molecules may provide a miracle if they can halt the development of neurodegenerative diseases. So, drugs from plant origin are required to be discovered to replace these chemically synthesized drugs as the safety profile of these natural phytoconstituents is wider enough even at their higher doses. This article reviews the therapeutic potential of plant-derived medicines, which possess potential therapeutic effects against various neurological diseases such as Epilepsy, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), Multiple sclerosis (MS), Depression, and Anxiety. Herbs used in these diseases are matrine, physostigmine, caffeine, morphine, berberine, galantamine, piperine, and other alkaloids. These alkaloids act positively by several mechanisms like dopaminergic and nicotine agonist, acetylcholinesterase and butyrylcholinesterase inhibitor, NMDA antagonist, inhibitors of α-synuclein aggregation, anti-oxidant, MAO inhibitors, and anti- amyloid agents to ameliorate pathophysiology of neurological diseases. Dur to their therapeutic impact they are now available in market but opportunities exist to overcome technological challenges.

Full text

01004
The Rapeutic impact of alkaloids in neurological diseases:
A promising key molecule
Sukhanpreet Kaur1, Gagandeep Kaur1, Ruhi Rana1, Bimlesh Kumar1*, Indu Melkani1, Shubham Kumar1, Narendra Kumar
Pandey1, Saurabh Singh1, Dileep Singh Baghel1, Kardam Joshi2, Dhara Patel2, Omji Porwal3
1School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
2Topical Research and Development, Amneal Pharmaceuticals, Piscataway, New Jersey, USA
3Faculty of Pharmacy, Tishk International University, 100 mt. Street, near Filkey Baz (Square), across Qazi Muhammad,
44001, Erbil, KRG/IRAQ
*Corresponding author:bimlesh1pharm@gmail.com
Abstract: Neurological disease is a disorder of the nervous system. It may be associated with the central
nervous system or peripheral nervous system. Neurological problems are disorders of specific neurons or
loss of neurons with their structural or functional impairment. The specific reason for neurological diseases
may be genetic defects, congenital disorders, infections, and environmental health issues. No doubt, there are
various well-known synthetic medications are available for the treatment of neurological disorders but they
exert many toxicities and ADRs (Adverse Drug Reactions). The identification of compelling and promising
molecules may provide a miracle if they can halt the development of neurodegenerative diseases. So, drugs
from plant origin are required to be discovered to replace these chemically synthesized drugs as the safety
profile of these natural phytoconstituents is wider enough even at their higher doses. This article reviews the
therapeutic potential of plant-derived medicines, which possess potential therapeutic effects against various
neurological diseases such as Epilepsy, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s
disease (AD), Multiple sclerosis (MS), Depression, and Anxiety. Herbs used in these diseases are matrine,
physostigmine, caffeine, morphine, berberine, galantamine, piperine, and other alkaloids. These alkaloids act
positively by several mechanisms like dopaminergic and nicotine agonist, acetylcholinesterase and
butyrylcholinesterase inhibitor, NMDA antagonist, inhibitors of α-synuclein aggregation, anti-oxidant, MAO
inhibitors, and anti- amyloid agents to ameliorate pathophysiology of neurological diseases. Dur to their
therapeutic impact they are now available in market but opportunities exist to overcome technological
challenges.
Keywords: Neurological diseases, Plant-derived alkaloids, Phytoconstituents, Neuroprotection.
1. Introduction
Worldwide, neurological disorders (ND) cause a huge health burden as it is cureless to date. Physicians, pharmacists, scientists,
and patients of ND complain about its therapeutic approach due to unsatisfactory relief and increased mortality as well as
morbidity. ND is disorders of the central and peripheral nervous systems. It affects the brain, spinal cord, peripheral nerves, nerve
roots, autonomic nervous system, cranial nerves, muscles, and neuromuscular junction 1. It ranges from Alzheimer’s disease
(AD) and different types of dementia, stroke, migraine, multiple sclerosis (MS), Parkinson's disease (PD), epilepsy (EPL),
depression, anxiety, Huntington’s disease (HD), and traumatic disorders including neuropathic pain (NP). Every year, greater
than 6 million people die due to stroke, especially in Low and Middle Income-Countries (LMICs) and about 50 million people
suffer from epilepsy 1. It is revealed that globally, about 47.6 million people suffer from dementia with the addition of 7.7 million
new reports every year, and, AD is the most common form of dementia (60-70% of total cases) 1 and the occurrence of migraines
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© The Authors, published by EDP Sciences. This is an open access article distributed under the terms of the Creative Commons Attribution
License 4.0 (https://creativecommons.org/licenses/by/4.0/).

is greater than 10%.Various known chemical medications/drugs are available for ND and are effective, but they are well known
to provide only symptomatic relief for a short period and also possess severe toxicities with adverse drug reactions (ADRs). So,
to overcome these side effects nowadays plant-based medications are in trend and their importance is increasing day by day.
Plant-based phytopharmaceuticals are less expensive, safe, and have multiple targets by which ND can be treated in the best
possible ways. ND is commonly known as neurodegeneration which accounts for specific loss of neurons as a result of these
impairments in normal function with alterations in the normal architecture of neurons are observed. Hence it can be stated that
there are multiple mechanisms are involved to develop ND and we need one or more phytopharmaceutical molecules with
multiple therapeutic targets to treat ND. Plant-based medications were used for a long time for neural and other diseases also.
Herbal medicines and their phytochemicals are known as potent neuroprotectors against various brain disorders.
Fig1. Treatment spectrum of alkaloid in terms of neurological diseases
Alkaloids are plant-derived (secondary metabolites), naturally occurring nitrogen-containing organic compounds. It exhibits good
efficacy against several ND like PD, AD, Schizophrenia, HD, depression, anxiety, and EPL. The very first alkaloid discovered
was morphine in the 19th century by modern chemistry, followed by other alkaloids like caffeine, nicotine, and codein. A very
rich source of alkaloids belongs to plant families of Ranunculaceae (buttercups), Amaryllidaceae (amaryllis), Papaveraceae
(poppies), and Solanaceae (nightshades) 2. Alkaloids can be mainly classified according to their chemical structure like indole
Quinolines, isoquinolines, pyridines, tropanes, terpenoids, pyrrolidines, steroids, and pyrrolizidines alkaloids. Alkaloids help
in the management of ND due to their antioxidants properties that protect the cells of the brain from increased stimulation of
neurotransmitters (Fig.1.).
2
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The present review focus on the fundamentals of ND, sources of alkaloids, an underlying mechanism to treat different types of
ND with its therapeutic impact from preclinical to clinical trials and present marketing scenario.
1.1. Neurological diseases (ND)
Dementia is one of the neurodegenerative disorders, that leads to the dysfunction of higher cortical functions, including
orientation, memory, language, thinking, learning capacity, and, judgment. It generally occurs in older people (>65 years). The
most common form of dementia is AD, which is marked by dementia with poor coordination, improper or blurred speech, and,
stoppage of executive functions. It is characterized by neurofibrillary tangles, hyperphosphorylated and clamped tau protein, and
amyloid-beta plaques. A serious feature of AD is severe neuroinflammation along with increased activated astrocytes and
microglia, which further releases neurotoxic cytokines like interleukin-1, tumor necrosis factor-α (TNF-α), interleukin-6,
interferon-γ, reactive carbonyl, nitrogen, and oxygen species which damages the other neurons also 2.
Like dementia, PD is also a ND, caused by the substantial diminution in dopamine and reduction in dopamine neurons in the
substantia nigra of the brain. Mitochondrial syndrome and oxidative stress are other causes of PD. It results in motor and non-
motor clinical features. Its motor hallmarks are rigidity, tremor, bradykinesia, and postural hypotension whereas, non-motor
symptoms include speech difficulties, gait freezing, falls and, swallowing difficulties 3.
Epilepsy (EPL) is a seizure disorder that can be defined as “a transient occurrence of signs or symptoms due to abnormal
excessive or synchronous neuronal activity in the brain” 4. The main reasons for EPL can be tumors and suffering in the brain,
stroke, diseases caused by infectious agents, and sclerosis in the hippocampus. The secondary causes for EPL include
autoimmune diseases, hereditary concerns, and, defects in the cortical region of the brain. It is interesting to note that the
prevalence of EPL is higher in low-income countries (LICs) which may be due to endemic conditions like neurocysticercosis and
birth defects. In high-income countries (HICs), the primary prevention in HICs should be the cessation of further seizures as they
can cause additional mortality and morbidity 4.
Globally, there are around 264 million patients affected by depression 1. Clinical features of depression are loss of interest and
concentration, social isolation, anxiety, sadness, sleep disturbances (mostly insomnia, excessive sleepiness is less), and fatigue.
Hormonal and chemical imbalance are causative factors for depression like a decrease in serotonin level and a decrease in
norepinephrine and dopamine level, as these hormones are necessary for emotional stability and functioning of the brain 1.
Undoubtedly, many antidepressant medications are available for its management but they also have higher side effects.
Anxiety is a usual reaction under pressure, danger, or when coping with challenging conditions like exams or interviews and
there is hyper activation of subcortical fear along with improper regulation from the prefrontal cortex. Hence, anxiety
disorders are panic disorder, generalized anxiety disorder, phobias, obsessive-compulsive disorder, post-traumatic stress disorder,
a social anxiety disorder. As anxiety is related to a group of conditions not a single disorder, the clinical features vary from
person to person, i.e. along with fear and nervousness, some may have chest pain, difficulty in respiration, and, palpitations 5.
Huntington’s disease (HD) is a rare kind of neurodegenerative disease. It is an inherited disorder of autosomal dominant trait in
which there is neuronal cell death, especially in the striatum and cerebral cortex. Clinically HD is manifested by a decrease in
motor and cognitive ability, chorea (slowly spreads to other muscles also), and suicidal risk (depression) 6. Secondary symptoms
include dysfunction of the autonomic nervous system and loss of weight 7.
Multiple sclerosis (MS) is a chronic autoimmune, neurological disease of the CNS, militated axons are the main target of this
disease therein destroys the axons and myelin to varying extents. In MS there is chronic inflammation occurs with scars and
plaques in the white matter of the CNS. Other signs of MS are optic neuritis, fatigue, sexual problems, and bladder dysfunction 8.
Schizophrenia is a severe mental illness characterized by hallucinations, delusions, and disorganized thinking. Although the
etiology of schizophrenia is unknown, ideas have been proposed that the demyelination of white matter is the reason 9 with loss
of cortical grey matter 10, decreased hippocampus volume, the amygdala, temporal, and frontal lobes, and enlarged ventricular
regions. Reduced ATP availability is followed by mitochondrial failure inhibits the activity of the Na+/K+ ATPase, which
maintains the membrane potential, causing prolonged depolarization and enhancing receptor activity by oozing magnesium from
the N-methyl-D-aspartate receptors (NMDAR) 11.
1.2Therapeutic spectrum of alkaloids
Nature has provided many active ingredients which give health benefits to society. The crude form of the drugs, as well as
pharmaceutically developed formulation, supports the health sector worldwide. Plants and their metabolites help in the treatment
of various diseases of humans and animals (Table.1.). Now a day’s most of the research is centric to plant products. The
secondary metabolites of the plant are alkaloids, terpenoids, sterols, tannins, and phenols. These components help in the survival
and reproduction of the plants also 12,13.
Alkaloids are a very important kind of secondary metabolite. They are chemically nitrogen-containing compounds having diverse
therapeutic potential. A typical kind of alkaloid has basic chemical nature. The metabolites of alkaloids have behavioral effects
(Cotinine, Nicotine Nc-oxide, and cotinine N’-oxide), anticholinergic effects (Noratropine), sedative, antiemetic (Norscopine,
scopine, tropic acid, aponorscopolamine), antiepileptic and central nervous system stimulant (Benzoylecgonine (BE), and
ecgonine methyl ester (EME), etc. Due to enhanced beneficial effects, there are many alkaloids available in the market which
include nicotine, cystine, atropine, scopolamine, cocaine, quinine, quinidine, papaverine, berberine, morphine, codeine, reserpine,
ergotamine, etc (Table.1.) 14–16. The therapeutic application of different alkaloids in the ND is summarized in Table.2. It is very
important to understand that role of alkaloids in humans and animals.
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Table1. Alkaloids and their metabolites
Alkaloids
Pharmacologi
cal activity
Metabolite
Reference
s
Modification
of behavior
Cotinine, Nicotine
N’-oxide and cotinine
N’-oxide
142,143
Anti-
cholinergic
response
Noratropine, atropine-
N-oxide
(equatorial isomer),
tropine and tropic
acid
3
Sedative,
antiemetic
Norscopine, scopine,
tropic acid,
aponorscopolamine
144–146
CNS
stimulant,
anti-
convulsion
Benzoylecgonine
(BE) and ecgonine
methyl ester (EME)
[21,150,15
1]
4
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Analgesic and
anti-
inflammatory
3-hydoxyquinine, 2 ׳-
quininone, (10S)
and (10R)-11-
dihydroxydihydroquin
ine
148,149
Antimalarial
3-Hydroxyquinidine
and quinidine Noxide
150
Inhibit
parasympathet
ic ic nervous
system
(3S)- hydroxy-
dihydroquinidine (3-
OH-DHQ), 11-
hydroxydihydroquinid
ine
(11-OH-DHQ), 10-
(3S)- hydroxy-
dihydroquinidine (10-
OH-DHQ)
151
5
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Upregulated
expressions of
p53
Berberrubine,
thalifendine,
dimethlyleneberberine
, jatrorrhizine
152,153
Analgesic
Codeine glucuronide,
norcodeine
154
Morphine-3-
glucuronide,
normorphine
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Sympathetic
stimulation
Ephedrine,
pseudoephedrine,
phenylpropanolamine,
155,156
Analgesics,
CNS stimulant
Paraxanthine,
Theophylline, and
theobromine, 1,3,7
trimethyluric acid
157,158
Cholinergic in
action
Pilocarpic acid, 3-
hydroxypilocarpine
159
Bronchitis
Metabolites1 (m/z
340), metabolites2
(m/z
354), metabolites3
(m/z 370),
metabolites4 (m/
z 356), metabolites5
(m/z 372),
160
7
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Antiarrhythmi
cs
2-dehydrosparteine
and 5-
dehydrosparteine
13
Acts on
sensory
system
Vanillylamine,
vanillin, 16-
hydroxycapsaicin, 17-
hydroxycapsaicin, and
16,17-
dehydrocapsaicin
161,162
Cholinergic in
action
Acetylcholine,
betanine,
glycerophosphorylcho
line,
sphingomyelin,
phosphatidylcholine
163
Alpha
adrenoreceptor
blocking effect
Monohydroxylated
metabolites and
dihydroxylated
metabolites
164
8
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Cholinergic
action enhance
and
antiadrenergic
10-hydroxy-
yohimbine, 11-
hydroxyyohimbine
165
Stimulate
cerebellum
2-hydroxystrychnine,
Strychnine N-oxide
13,159
Anti-
inflammatory
and analgesic
in action
Brucine N-oxide
166,167
Treat cancer
and viral
infection
Cephaeline (60-O-
demethylemetine), 9-
Odemethylemetine,
and 10-O-
demethylemetine
168
9
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Stimulant for
respiratory
system
Methylxanthine, 2-
Methylxanthine, 3,7-
Dimethyluric acid
169
Relaxes
smooth
muscles
Methyluric acid
Table 2: Classes of alkaloids, source, and their target ND
Name of
Alkaloid
Structure
Class of
Alkaloid
Plant Sources
Therapeu
tic
Purposes
Major
Toxicities
Referen
ces
Caffeine
Methylxanth
Coffea
AD(300–
Caffenism
6, 18
ines
arabica
400
1200 mg,
(Rubiaceae)
mg/kg)
(Restlessness,
PD(200-
anxiety,
400
insomnia,
mg/kg)
tachycardia,
psychomotor
disturbances)
Berberine
Isoquinoline
Berberis
AD (100-
Diarrhea,
2, 6, 170
vulgaris,
200
Constipation &
Berberis
mg/kg)
Neonatal
aristata
PD (50-
hemolytic
(Berberidacea
100
jaundice (If
e)
mg/kg)
taken during
HD (40
pregnancy)
mg/kg)
>1.5 g/day
Epilepsy
(25-100
mg/kg)
10
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Matrine
Quinolizidin
e
Sophora
flavescens
(Fabaceae)
AD (100-
200
mg/kg)
PD (200
mg/kg)
MS (200
mg/kg)
Anxiety
Depressio
n (120
mg/kg)
Neurotoxicity
&
Hepatotoxicity
> 150 mg/kg
25, 26, 27
Morphine
Isoquinoline
Papaver
somniferum
(Papaveraceae
)
AD (1 μm)
Addictive in
nature,
Vomiting,
nausea (in
pregnant
women) &
Damage
pyramidal cells
(> 200-300μg)
2, 6, 28,
171
Apomorphine
Aporphine
Papaver
somniferum
(Papaveraceae
)
PD (3
mg/kg)
Hypersensitivit
y,
Hemolytic
anaemia &
Bronchoconstri
ction (> 5 mg)
6, 29, 30
Piperine
Piperidine Piper longum,
Piper nigrum
(Piperaceae)
AD (20
mg/kg)
PD
Epilepsy
(20
mg/kg)
Burning
sensations in
stomach and
throat (> 330
mg/kg)
6, 32, 31
Galantamine
Isoquinoline
Galanthus
nivalis,
Galanthus
woronowii
(Amaryllidac
Seae)
AD
(26mg/kg)
Vomiting,
Nausea,
Diarrhea, loss
of appetite &
headache
(120 mg/l)
2, 6, 34, 3
Rhynchophylli
ne &
Isorhynchophy
lline
Tetracyclic
oxindole
Uncaria
rhynchophylla
(Rubiaceae)
AD (20
mg/kg)
PD
Sedation &
Hypotension
(50 mg/kg in
rats and 3.3
mg/kg in mice)
36, 37, 38,
3
Nicotine
Pyridine Nicotiana
tobaccum
(Solanaceae)
AD
PD
Disrupt
mitochondrial
membrane &
produce
apoptosis
6, 40, 42,
41
11
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Brahmin
Bacopa
monnieri
(Scrophularia
ceae)
AD (20-80
mg/kg)
PD (40
mg/kg)
Epilepsy
Mild nausea &
gastrointestinal
problems
43, 44, 45,
48
Physostigmine
Pyrroloindol
e
Physostigma
venosum
(Leguminosae
)
AD
PD
Headaches,
dizziness,
diarrhea,
nausea, high
BP & heart rate
>0.04 mg/kg
52, 55, 57
Huperzine A
Lycopodium
alkaloid
Huperzia
serrata
(Huperziaceae
)
AD
PD
Contraction &
twitching of
muscle fibres,
cramping, high
BP, slow HR,
frequent
urination
>4mg/kg
59, 60, 172
Vinpocetine
Apovincami
ne
Vinca minor
(Dogbanes)
Ischemia
(10
mg/kg)
AD
(60mg/day
)
PD
Epilepsy
>100 mg/kg
Stomach pain,
headache,
nervousness,
flushing of face
& weakened
immune system
63, 66, 68,
74
Arecoline
Pyridine
Areca catechu
L (Arecaceae)
Schizophr
enia (7.5
mg/g)
100 mg/kg,
cytotoxic and
inflammatory
76, 79
Salsoline
Isoquinoline
Chenopodiace
ae
AD
54, 81
Lobeline
Piperidine
Lobelia inflate
Lobelia
nicotianaefoli
a
(Campanulace
ae)
PD (3
mg/kg)
Epilepsy
(5-20
mg/kg)
Nausea,
bradycardia,
tingling & oral
numbness
83, 84, 85
12
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Nantenine
Aporphine
Nandina
domestica
(Berberidacea
e)
Epilepsy
(20-50
mg/kg)
Ataxia &
convulsions
(75-105 mg/kg)
86
Harmine
β-carboline
(indole)
Banisteriopsis
caapi &
Peganum
harmala
(Nitrariaceae)
AD (30
mg/kg)
Depressio
n (10-20
mg/kg)
Cytotoxicity
(100 µg/ml)
92, 89
Geissoschizolin
e
Indole Galanthus
nivalis &
Geissospermu
m vellosii
(Apocynaceae
)
AD Cytotoxicity
95
Jateorrhizine
Isoquinoline
Coptis
chinensis
(Ranunculace
ae)
AD (5-10
mg/kg)
96
Ibogaine
Indole Tabernanthe
iboga
(Apocynaceae
)
Substance
use
disorder
PD (10
µmol/L)
Acute motor
impairment,
cardiac toxicity
> 5 mg/kg
173
Rutaecarpine
Indole Evodia
rutaecarpa
(Rutaceae)
AD
Cerebral
ischemia
(1-2
mg/mL)
slow down the
blood clotting,
increase the
chances of
bruising &
bleeding
102, 174,
103,
Acetylcorynoli
ne
Corydalis
bungeana
(Papaveraceae
)
PD (100
mg/kg)
>10 mM
175,176
Sinapine
Sinapic acid
choline ester
Raphanus
sativus
(Brassicaceae)
AD
(+)-erythravine
and (+)-11-α-
hydroxyerythr
avine
Erythrine
Erythrina
mulungu
(Fabaceae)
Epilepsy
(1-3μg/μl)
107, 109,
108
13
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Montanine
Isoquinoline
Hippeastrum
vittatum
(Amaryllidace
ae )
Epilepsy
(10–60
mg/ kg)
Depressio
n(1-10
mg/kg)
Anxiety
(1-3
mg/kg)
GIT
disturbance
113, 111
Coptisine
Isoquinolin
e
Coptidis
rhizome,
(Ranunculace
ae)
AD (50
mg/kg)
Haemolytic
jaundice,
nausea,
vomiting,
shortness of
breath and
convulsion
(4.89 g/kg)
116
Palmatine
Isoquinoline
Phellodendro
n amurense
(Rutaceae),
Coptis
Chinensis
(Ranunculace
ae), Corydalis
yanhusuo
(Papaveraceae
)
AD (5.21
mg/mL)
Depressio
n (15-20
mg/mL)
Hepatotoxicity,
Damage to
DNA by
oxidative
stress,
apoptosis (200
mg/mL)
118, 119,
123
sLupanine
Quinolizidin
e
Lupinus
angustifolius
(Fabaceae)
AD
126, 125
Asparagamine
A
Asparagus
racemosus
(Fabaceae)
AD (50-
200
mg/kg)
Amnesia
(100-200
mg/kg)
127, 129
1.3 Therapeutic potential of caffeine in ND
It is a methyl xanthine derivative, extracted from seeds of Coffea arabica (Rubiaceae) and widely used as a psych stimulant in the
form of soft drinks, tea, and coffee 6. After administration, It shows fast absorption from the gastrointestinal tract and reaches the
circulation, and further, it rapidly gets into all the body tissues. It also exhibits penetration to the different barriers such as the
blood-brain, blood-placenta, and, blood-testis barrier. Its CNS stimulation activity mainly involves increase in cerebral energy
metabolism, cortical activity, and levels of extracellular acetylcholine which results in improvement in alertness 6. Caffeine
shows anti-inflammatory and anti-oxidative action and also enhances behavior like mood, vigilance, arousal, and, attention 6.
Caffeine cause neurotoxicity when act as an adenosine A2A receptor antagonist and its overconsumption known as “Caffenism”
2,17.
1.4 Role of caffeine in AD
Due to its psych stimulant activity, caffeine (300-400 mg in the form of coffee or tea) is known to decrease the risk of cognitive
impairment and risk of AD development 18. In AD, the production of amyloid-beta 42 (Aβ42) isoform is there due to altered
activity of γ-secretase caused by presenilins 1 & 2 gene mutations. Caffeine decreases the level of presenilins 1, and Aβ
deposition in the hippocampus and cortex region. In the hippocampus caffeine decreases proteolytic tau fragments and tau
phosphorylation, preventing neuronal cell death due to neurofibrillary tangles 6. Caffeine reduces the Aβ neurotoxicity and
protects the neurons of the basal forebrain and cerebellar granule by diminishing the expression of caspase-3 2. A
“Cardiovascular Risk Factors, Aging, and Dementia” (CAIDE) study revealed that at midlife, taking 3-5 cups of coffee daily is
related to a 65% lower risk of dementia 19.
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1.5 Role of caffeine in PD
Caffeine increases locomotors activity and neuronal death caused by excitotoxicity by blocking of adenosine A2A receptor
(microglial receptors). Increase in the number of activated microglial cells results in neuroinflammation and deleterious effect on
dopaminergic neurons and caffeine enhances dopamine neurotransmission 6.
1.6 Therapeutic potential of Berberine (BBR) in ND
BBR is an Indian and Chinese herb, that belongs to the class of isoquinoline. It can be extracted from stems, roots and, the bark
of various plants such as Berberis vulgaris (barberry), Berberisaristata (tree turmeric), Hydrastis canadensis (Goldenseal) and,
Coptischinensis (copies or golden thread). Along with a neuroprotective action, berberine also exerts anti-microbial, anti-
hypertensive, anti-diarrheal, and anti-diabetic action 2,6.
1.7 Role of BBR in AD
Various studies show that BBR blocks both AChE and BChE and also has higher selectivity for both enzymes. So, it enhances
cholinergic stimulation and is used to improve cognitive impairment in AD 2. BACE-1 (Beta-secretase 1) is Amyloid Precursor
Protein (APP) cleaving enzyme and leads to the production of Aβ so, BBR reduces the action of BACE-1 and reduces
neurodegeneration in the hippocampus 6. In an AD model of rabbits, BBR enhances survival rate and decreases hippocampal
injury by blocking the β-secretase activity. It also decreases learning deficits and boosts long-term spatial. BBR has anti-
oxidative actions, inhibits lipid peroxidation, and decreases oxidative stress 20.
1.8 Role of BBR in PD
BBR inhibits the damage of dopaminergic neurons by increasing motor stability 6. It also reduces the damage of substantia nigra
dopaminergic neurons and inhibits hippocampal apoptosis, therefore preventing memory and balance loss in PDl 21. It is well
known that MAO-A & B (Monoamine oxidase) degrades dopamine and is a causative factor in PD. It is also documented that
BBR can act as an MAO inhibitor and it is safer than other drugs of the same category 22.
1.9 Role of BBR in EPL
Well-known antiepileptic drugs have many ADRs and do not provide sufficient relief. Hence, the importance of phototherapy
increases. Berberis vulgaris species of BBR is used in EPL. It acts as an NMDA receptor antagonist and inhibits the action of
excitatory neurotransmitters such as glutamate 23.
1.10 Role of BBR in HD
It is a rare neurodegenerative disease due to misfolding of proteins and to prevent this BBR can unregulated autophagy and
decreases the misfolding of proteins 24. It is reported that the stimulation of autophagy action enhances motor and movement
coordination.
1.11 Therapeutic potential of matrine in ND
Matrine is a naturally derived quinolizidine alkaloid, extracted from a Chinese herb Sophora flavescens (Legumes). Various
studies showed that matrine has less half-life and less oral bioavailability. Matrine possesses a wide range of therapeutic activities
like neuroprotective actions, anti-inflammatory, anti-allergic, anti-oxidant, hepatoprotective, anticancer, antiviral, and anti-
fibrotic. Although it is used widely in several diseases studies revealed that it also has ADRs like neurotoxicity and
hepatotoxicity 25.
1.12 Role of matrine in AD
Matrine decreases IL-1b concentration, increasing energy metabolism, inhibiting neuronal apoptosis, and protecting the structure
of mitochondria in AD. The cognitive phenomenon can be modified by inhibiting Ab/RAGE (Receptor for Advanced Glycation
End-Products) pathway 26. Moreover, matrine can retain and strengthen the Aβ monomers’ cellular nutrition by blocking the
Aβ42 aggregation and combining it with Aβ monomers 25.
1.13Role of matrine in PD
Matrine has a protective action in MPTP-induced rats and inhibits the overstimulation of Nrf2 (Nuclear factor erythroid 2),
responsible for the regulation of antioxidant proteins 26.
1.14 Role of matrine in MS
Matrine (200mg/kg/day) recovers the experimental autoimmune encephalomyelitis (EAE) symptoms in animal models 25. It
increases the local production of neurotropic 3 in astrocytes, oligodendrocyte precursor cells, and, microglia to protect neural
cells 27.
1.15 Role of matrine in anxiety and depression
Matrine helps to reduce symptoms, studied on a burn injury model of a mouse. It blocks the JNK (c-Jun N-terminal Kinase)
stimulated apoptosis and oxidative stress. It is also known to stimulate hippocampal Akt/mTOR pathways in mice to exhibit
antidepressant action 27.
1.16Therapeutic potential of morphine in ND
It is an isoquinoline alkaloid, extracted from capsules of Papaver somniferum (Papaveraceae) and offers an analgesic action used
in serious to extreme pain conditions. They mainly work by four types of opioid G protein-coupled receptors, “μ, δ, κ, and the
nociception orphanin peptide receptor” 2. It exerts its analgesic action through the μ-opioid receptor (MOR) 6. Several studies
revealed that morphine has a beneficial effect in injuries on the neuronal system but due to its addictive nature use of morphine is
limited and restricted 28.
1.17Role of morphine in AD
Morphine decreases oxidative stress, neuroinflammation caused by microglia and enhances the release of estradiol. It brings
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upregulation of heat shock protein-70 to reduce the intracellular toxicity produced by amyloids. Stimulation of μ-opioid receptors
reduces Aβ neurotoxicity and enhances the level of GABA in brain synapses through the TOR (Mammalian Target of Rapamycin
pathway). Morphine can reverse the electrophysiological alternations like resting membrane potential and capacitance caused by
intracellular Aβ 28.
1.18 Therapeutic potential of Apo morphine in ND
It is an aporphine alkaloid, produced by the heating of morphine with mineral acids at the temperature of 140-160℃ 6. It is the
oldest non-ergot dopamine agonist having an affinity for D1 and D2 receptors and has a short half-life. It absorbs rapidly and
fully from the subcutaneous route and produces action within 4 to 12 minutes. In marketed preparations of Apo morphine,
sodium metabisulphite is present which may lead to hypersensitivity reactions, hemolytic anemia, and, bronchoconstriction.
Ulcerations, tenderness, erythema may develop at the site of injection 29.
1.19 Role of Apo morphine in PD
Apomorphine acts as a dopamine receptor agonist by acting on D1 and D2 receptors. It is given subcutaneously with the use of a
pen-inject system to stop ‘OFF periods’ and also with a pump device for constant delivery to ameliorate motor complications in
advanced patients of PD 29. On Apo morphine infusion, there is upgrading in cognition, attention, hallucinations, mood, and
impulse control disorders that may develop or resolve 30.
1.20 Therapeutic potential of piperine (PIP) in ND
It is an alkaloid extracted from Piper longum (long pepper) and Piper nigrum (black pepper, from the Piperaceae family. Piperine
has various pharmacological actions like anticonvulsant, antidepressant, anti-oxidant, antifungal, antipyretic, anti-inflammatory,
insecticidal, analgesic, antihypertensive, and antitumor 31. In a study, it was found that at a low dose, PIP can increase
hippocampus neuronal density.
1.21 Role of PIP in AD
It is well documented that PIP can enhance cognition and decrease oxidative stress in the hippocampus of the AD rat model 32.
Piperine works by blocking enzymes such as AChE andβ-secretase and at 20 mg/kg shows synergistic action with quercetin (20,
40, and 80 mg/kg) in decreasing oxidative stress and improving cognition 6.
1.22 Role of PIP in PD
It has been stated that piperine can block MAO-B enzyme which in turn increases the dopamine level, MAO B is involved in its
degradation 6. It also enhances the balance and coordination in 6-ODHA (6- Hydroxydopamine) causing parkinsonian in rats and
it also inhibits inflammatory mediators like interleukin-1 β and tumor necrosis factor-α (TNF-α) 31.
1.23 Role of PIP in EPL
PIP alters the level of GABA, Serotonin, Norepinephrin and inhibits the tonic-clonic seizures by increasing the cortical and
hippocampal GABA and serotonin concentrations. It is also identified that PIP can blocks calcium and sodium channel 31.
1.24 Therapeutic potential of galantamine in ND
Galantamine (galanthamine) can be isolated from various species of plants such as Galanthus nivalis (snowdrop), Galanthus
woronowii (Amaryllidaceae), Narcissus tazetta (daffodil) and Lycoris radiate (red spider lily) 6. It is used in NP and also act as
an anesthetic 2. Vomiting, nausea, and GIT disturbances are its common side effects 33.
1.25 Role of galantamine in AD
Galantamine can decrease the occurrence of AD through neuroprotection and neurogenesis. It works by inhibiting AChE
selectively (53 folds greater selective than BChE) and reversibly, therefore improving the cholinergic neurotransmission by
decreasing the acetylcholine degradation 26. Galantamine attached to the AChE leads to enhancement in the level of ACh in the
synaptic cleft as its catabolism is reduced. 24mg/day of galantamine enhances understanding and cognition with no
hepatotoxicity 34. In AD, there is nAChR, α7 subtype (Nicotinic Acetylcholine Receptors) dysfunctioning leads to impairment in
memory and learning while galantamine modulates nAChR action leads to potentiation of nicotinic neurotransmission. It
decreases Aβ gathering, cytotoxicity and can scavenge reactive oxygen species, which protects neurons from oxidative
hemorrhage 35.
1.26 Therapeutic potential of rhynchophylline and isorhynchophylline in ND
Rhynchophylline and isorhynchophylline are tetracyclic oxindole alkaloids, extracted from the plant Uncaria rhynchophylla. It is
reported that they exert positive effects on neurological diseases like dementia, epilepsy, and amnesia 36. They possesses
anticoagulant and calcium channel blocking effect.
1.27 Role of rhynchophylline and isorhynchophylline in AD
These drugs reduce oxidative stress and inhibit cellular apoptosis 37 to provide neuroprotective action and decrease Aβ
neurotoxicity. Isorhynchophylline can overturn the Aβ activated phosphorylation of Akt, cAMP response binding protein, and
GSK-3β (Glycogen synthase kinase) signaling proteins. It improves behavioral and cognitive impairments in AD-induced rats.
Both drugs also reduce the hyperphosphorylation of tau protein and calcium overload 38.
1.28 Role of rhynchophylline and isorhynchophylline in PD
Isorhynchophylline cleaves the α-synuclein which is the main part of the lewis body and protects against the lysosome-autophagy
pathway 39. A decrease in the level of dopamine and its metabolites in MPTP-induced mice was ameliorated by rhynchophylline
effectively. In the same study, it is also stated that MPTP enhances dopamine catabolism via MAO, which is also blocked by
rhynchophylline by reducing the DOPAC/DA ratio 3.
1.29Therapeutic potential of nicotine in ND
Nicotine is a pyridine alkaloid, extracted from Nicotianato baccum (Solanaceae). It exerts extensive pharmacological actions in
the central nervous system and the peripheral nervous systems (PNS) mediated by the activation of nicotinic acetylcholine
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receptors (nAChRs). It decreases neuroinflammation and oxidative stress to reduce the extent of pathological conditions. It is
interesting to note that, the use of tobacco and cigarette smoking reduces the prevalence of AD and PD 40. It also produces
toxicity by disrupting mitochondrial membrane and by producing reactive oxygen species. It also induces apoptosis by inducing
caspase-3 action 6.
1.30 Role of nicotine in AD
Nicotine shows its potential efficacy in increasing the neuroprotection by up-regulating of α4 and α7nAChRs intensity. Nicotine
can reduce AD pathology due to presence of cotinine 40. It prevents memory loss by blocking the Aβ peptides accumulation 6.
1.31 Role of nicotine in PD
Nicotine protects against nigrostriatal damage, which could justify the well-documented drop in PD. It can also reduce L-dopa-
induced aberrant involuntary movements due to an interaction at nAChRs 41. Unilaterally lesioned 6-hydroxydopamine (6-
OHDA) rats and MPTP-treated monkeys model of PD, nicotine was given before and/or after nigrostriatal injury to see
restoration of striatal dopaminergic function. In another study nicotine found to improve behavioral deficits and mitigated lesion-
induced losses of striatal dopaminergic markers when rats received nicotine before and after a unilateral 6-OHDA lesion of the
medial forebrain bundle 42.
1.32 Therapeutic potential of brahmine in ND
Brahmine is extracted from fresh leaves and stem of the plant known as Bacopa monnieri (Brahmi), which belongs to the
Scrophulariaceae family. In Ayurveda, it is highly recommended for epilepsy, memory loss, insomnia, and mental stress. There
are several phytochemicals present in this herbal plant like brahmine, nicotine, herpestine, bacopasides III, IV, V, bacosides A
and B, saponins, betulic acid, polyphenols, and bacosaponins A, B, C, D, E, and F 43 that exerts several pharmacological benifits.
In vivo and in vitro studies revealed that these phytoconstituents inhibit lipid peroxidation thereby, producing antioxidant and
free radical scavenging action in the brain. It is well documented for its antioxidant, anti-inflammatory, anticonvulsant,
cardiotonic, bronchodilator, anxiolytic, and peptic ulcer protection properties 44.
1.33Role of brahmin in AD
The antioxidant and anti-stress activities of brahmine contribute to its neuroprotective function. In a study, conducted on an AD
transgenic mouse model (PSAPP mice), it was shown that the brahmine extract reduces the beta-amyloid-induced oxidative stress
pathway, inhibits AChE activity and decreases the Aβ levels in the brain 45. In addition to this it inhibits DNA damage and
oxidation in a dose-dependent manner in cultured rat astrocytes provoked by a nitric oxide donor 46.
1.34Role of brahmin in PD
In a study, authors studied the neuroprotective effects and antioxidant action of the brahmine in Drosophila model of PD 47. In
that study, brahmine was found to be highly effective against free radicals like nitric oxide, superoxide, and hydroxyl radicals.
Brahmine efficiently chelated iron and protects against deoxyribose oxidation. In low doses, brahmine treatment was found to
decreases the TNF-α and interleukin in LPS-induced N9 microglial cells 48.
1.35 Role of brahmine in EPL
In a model of pilocarpine-induced epilepsy in rats, there is considerable down regulation of NMDA R1 gene expression with
glutamate receptor function. In this model, Brahmin treatment reversed the NMDA R1 expression and glutamate receptor
binding alterations 49. In a following study from the same group, Brahmin was found to antagonize the up regulation of
hippocampal 5-hydroxytryptamine-2C (5- HT2C) receptors of pilocarpine-induced epileptic rats 50. Another research provides a
shred of evidence that intraperitoneal injections of brahmine at its higher doses given for 15 days exhibited pronounced
anticonvulsant activity 51.
1.36 Therapeutic potential of physostigmine in ND
Physostigmine is isolated from dried seeds of Physostigma venosum (Leguminosae family) having carbamate moiety that is
helpful in its pharmacological actions. It is well-known to treat AD and PD. Major side effects of physostigmine include
headaches, dizziness, vomiting, diarrhea, nausea along with a rise in blood pressure and heart rate 52.
1.37 Role of physostigmine in AD
Physostigmine is used in AD because of its ability to block BChE enzyme. Rivastigmine inhibit BuChE as well as AChE hence
have valuable clinical effect in AD. It is synthetic analog of physostigmine (H. Ferreira-Vieira et al., 2016). A physostigmine
derivative, Eptastigmine a heptyl-physostigmine tartrate known to block BChE and AChE but produces adverse effects on the
hematological system 55 while cymserine and bisnorcymserine inhibit BChE 56. Phenserine is a blocker of AChE and amyloid
precursor protein (APP) and also has lower toxicity than physostigmine 57.
1.38 Role of physostigmine in PD
As the expression of α-synuclein is increased in PD. Physostigmine has the good efficacy to lower an α-synuclein level in neural
cell lines 58.
1.39 Therapeutic potential of Huperzine A in ND
It is isolated from Huperzia serrata from Huperziaceae family. Phlegmariurus squarrosus is a member of Huperziaceae, its in
vitro tissue culture produces higher concentrations of huperzine A. Major adverse effects of huperzine A are contraction &
twitching of muscle fibers, cramping, high BP, slow HR, and frequent urination 59.
1.40 Role of Huperzine A in AD
Huperzine A is a potent competitive inhibitor of AChE and can inhibit AChE with an IC50 of 0.1 µM, which is approximately
1000-fold more potent than its inhibition of BChE 60. It was also found that (−)huperzine A is 70 times more potent in blocking
AChE than (+)huperzine A. Huperzine A can show a more prolonged inhibitory effect on AChE as compared to donepezil and
tacrine. Moreover it also acts as NMDAR antagonist and decreases glutamate excitotoxicity 61. The protective effect of huperzine
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against neuronal apoptosis in AD can also be attained by regulating the pro-apoptotic genes/proteins expression and rising the
anti-apoptotic genes/proteins expression 62.
Table.3. Marketed formulations of alkaloids for neurological diseases
Formulation
Name of
alkaloid
Dose
Composition
Application
Company name
Reference
Exelon Patch
10
Rivastigmine
4.6 mg and
9.5 mg
Rivastigmine, Vitamin
E, Silicone oil, Acrylic
copolymer
AD
PD
Novartis
Pharmaceuticals
Corporation
177
Reminyl ER
Galantamine
8,16,24 mg
Galantamine
hydrobromide, diethyl
phthalate,
ethylcellulose, gelatin,
hypromellose,
polyethylene glycol,
sugar spheres
AD
Janssen
178
NICOTROL®
Nicotine
10 mg/ mL
Nicotine, disodium
phosphate, sodium
dihydrogen phosphate,
citric acid,
methylparaben,
propylparaben, edetate
disodium
AD
PD
Smoking
cessation
Pfizer
179
NicoDerm CQ
Nicotine
21 mg
Ethylene vinyl acetate
copolymer,
polyisobutylene,
polyethylene
AD
Smoking
cessation
GlaxoSmithKline
180
MorphaBond
ER
Morphine
15,30,60,100
mg
Morphine sulfate,
hypromellose, xanthan
gum, microcrystalline
cellulose, sodium
alginate, alginic acid,
mannitol, colloidal
silicon dioxide,
magnesium stearate
AD
Daiichi Sankyo
Inc
181
Cognitol™
Vinpocetine
5 mg
Vinpocetine
Ischemia
AD
PD
Epilepsy
Sun Pharma
Laboratories Ltd
140
BioPerine®
Piperine
10 mg
Piperine
AD
PD
Sabinsa
Corporation
182
Marketed formulations of alkaloids for neurological diseases
To date, very a smaller number of alkaloidal products are available in the market for the ND. List of marketed alkaloids with their
formulation and manufacturing company given in Table.3. with their company names. When the drugs appear in the market it
exemplifies the clinical importance and proper pharmaceutical development of the molecule.[182-186]
2. Conclusion and future prospective
No doubt there are several drugs available for ND, but they do not have the efficacy to halt disease development, but they do
have a lot of negative effect to health. Various natural alkaloids exhibit the treatment of several ND such as PD, AD,
Schizophrenia, HD, depression, anxiety, and EPL by modulating neurotransmitters, possess anti-amyloid, antioxidant, anti-
inflammatory, anti-convulsing, and, anti-depressive efficacy. Hence, natural alkaloids are found safer than synthetic drugs.
Alkaloids show their neuroprotective action by various means such as dopaminergic and nicotine agonist, acetylcholinesterase
and butyrylcholinesterase inhibitor, NMDA antagonist, an inhibitor of α-synuclein aggregation, anti-oxidant, MAO inhibitors,
and anti-amyloid agents. In the future, there is a need to design more clinical trials for these alkaloids with the development of
Nano formulations. Finally, such kinds of approach will motivate the use a natural product.
ADRs Adverse Drug Reactions; HD Huntington’s Disease; PD Parkinson’s Disease; AD Alzheimer’s Disease; MS
Multiple Sclerosis; NMDAR N-methyl-D-aspartate receptors; MAO Monoamine Oxidases; ND Neurological Disorders;
LMICs Low and Middle Income-Countries; TNF-α Tumor Necrosis Factor-α; HICs High Income Countries; BE
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Benzoylecgonine; EME Ecgonine Methyl Ester; Aβ Amyloid-beta; BBR Berberine
GABA Gamma-Amino butyric Acid; GSK Glycogen synthase kinase; nAChRs Nicotinic Acetylcholine Receptors; 6-OHDA 6-
Hydroxydopamine; 5- HT2C 5-Hydroxytryptamine-2C; NF-κb Necrosis Factor–kappa Bis; PTZ Pentylenetetrazol; GFAP Glial
Fibrillary Acidic Protein; BChE Butyrylcholinesterase; AChE Acetylcholinesterase; DP Dopamine; ATP Adenosine
triphosphate; MDA Malondialdehyde; IDO Indoleamine 2,3-dioxygenase; NA-1 Neuraminidase-1; SOD Superoxide
Dismutase; CAT Catalase; MMSE Mini-Mental State Examination; HDS Hastgawa Dementia Scale; WMS Wechsler
Memory Scale; ESS Epworth Sleepiness Scale; UPDRS Unified Parkinson's Disease Rating Scale; MCI Mild Cognitive
Impairment; NS Central Nervous System; CGRP Calcitonin Gene-Related Peptide; hAChE human acetylcholinesterase;
hBChE human butyrylcholinesterase
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