ArticlePublisher preview available

Anti-insomnia Effect of a Polyherbal Formulation on P-chlorophenyalanine Induced Experimental Animal Model

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract and Figures

Sleep is a dynamic and controlled set of physiological and behavioural practices during which the stabilisation and restoration processes of the body take place properly. Therefore, sleep disorders, especially chronic insomnia, can harm an individual’s physical and mental health. However, the therapeutic alternatives are limited and possess severe side effects. Thus, in this study, we aimed to investigate the anti-insomnia effect of a polyherbal formulation (Sleep) (SLP) on p-chlorophenyalanine (PCPA) induced insomnia in rats. Intraperitoneal injection of PCPA induced the experimental condition, and the therapeutic effect of SLP was evaluated by studying the sleep pattern and expression of various neurotransmitters and receptors, along with neurotrophins. Moreover, insomnia-associated oxidative stress and inflammation were also studied. From the findings, we found that the SLP-supplemented animals improved their sleeping behaviour and that the major neurotransmitters, hormones, and receptors were maintained at an equilibrium level. Furthermore, the neurotrophin level was increased and pro-inflammatory cytokines were reduced. The evaluation of oxidative stress markers shows that the antioxidants were significantly boosted, and as a result, lipid peroxidation was prevented. The overall findings suggest that SLP can be used as an effective medication for the treatment of sleep disorders like insomnia as it triggers the major neurotransmitter system.
This content is subject to copyright. Terms and conditions apply.
ORIGINAL PAPER
Neurochemical Research (2024) 49:327–337
https://doi.org/10.1007/s11064-023-04035-2
awakenings, and a poor quality of life [2]. This condition
mostly shows gender disparities since women have insom-
nia more frequently than men [3]. In the modern era, the
prevalence of insomnia has been estimated to be 8–40%.
However, in the general population, 20–30% experience
dierent kinds of insomniac symptoms, and 8–10% of citi-
zens have severe insomnia [4].
Various researchers have proposed that stress is a closely
related condition that leads to dierent types of sleeping dis-
orders, including insomnia, that may arise after a stressful
experience or under stressful circumstances. Moreover, indi-
viduals with sleep problems are more susceptible to anxiety
and depression after any stressful situation than those with
a normal sleep cycle [5, 6]. These signs may coexist with
impaired memory and immune function, decreased mental
activity, a slower response time, and autonomic dysfunc-
tion [7]. Although the exact mechanism of insomnia is still
unknown, it is widely accepted that disturbances in sleep-
wake rhythm play a signicant role in the occurrence of
insomnia. There are dierent neurotransmitters and neural
pathways that aect the rhythm of the sleep–wake cycle.
Introduction
Sleep is regarded as one of the non-negotiable activities for
humans and is thought to be the most crucial component
in sustaining both physical and mental health. However,
several factors, such as mood disorders, ageing, decreased
amplitude of circadian cycles, and neurocognitive and hor-
monal abnormalities, substantially impair sleep quality
and result in insomnia [1]. Insomnia is a widespread epi-
demic that is marked by diculty in falling asleep, frequent
M Ratheesh
biochemistrystcp@gmail.com
1 Department of Biochemistry, St. Thomas College, Palai,
Kottayam, Kerala 686574, India
2 -Inorganic and Physical Chemistry, Indian Institute of
Science, Bangalore, Karnataka, India
3 -Research and Development, Kerala Ayurveda Ltd, Athani,
Ernakulam, Kerala, India
4 Katra group, Bangalore, Karnataka, India
Abstract
Sleep is a dynamic and controlled set of physiological and behavioural practices during which the stabilisation and res-
toration processes of the body take place properly. Therefore, sleep disorders, especially chronic insomnia, can harm an
individual’s physical and mental health. However, the therapeutic alternatives are limited and possess severe side eects.
Thus, in this study, we aimed to investigate the anti-insomnia eect of a polyherbal formulation (Sleep) (SLP) on p-chlo-
rophenyalanine (PCPA) induced insomnia in rats. Intraperitoneal injection of PCPA induced the experimental condition,
and the therapeutic eect of SLP was evaluated by studying the sleep pattern and expression of various neurotransmit-
ters and receptors, along with neurotrophins. Moreover, insomnia-associated oxidative stress and inammation were also
studied. From the ndings, we found that the SLP-supplemented animals improved their sleeping behaviour and that the
major neurotransmitters, hormones, and receptors were maintained at an equilibrium level. Furthermore, the neurotrophin
level was increased and pro-inammatory cytokines were reduced. The evaluation of oxidative stress markers shows that
the antioxidants were signicantly boosted, and as a result, lipid peroxidation was prevented. The overall ndings suggest
that SLP can be used as an eective medication for the treatment of sleep disorders like insomnia as it triggers the major
neurotransmitter system.
Keywords Insomnia · Neurotransmitters · neurotrophins · Inammation · Oxidative stress
Received: 12 August 2023 / Revised: 16 September 2023 / Accepted: 20 September 2023 / Published online: 28 September 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023
Anti-insomnia Eect of a Polyherbal Formulation on
P-chlorophenyalanine Induced Experimental Animal Model
SSheethal1· MRatheesh1· Svenia PJose1· SSandya2· SaralaSamuel3· JayashreeMadhavan4
1 3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... This is evidenced by increased GPx, SOD, and TAC levels, which may mitigate cold-induced OS and consequently enhance sperm resilience. BG contains several active compounds with robust antioxidant capacity, such as Benzofuran and octasiloxane [28], and androst-9(11)-en-17-one [31]. Moreover, benzoic acid was detected in BG, and a positive association between GABA and benzoic acid has been observed in bull spermatozoa [30]. ...
Article
Full-text available
This study investigated the cryoprotective effects of Lagenaria siceraria seed oil (BG) on rabbit sperm quality during a 72-hour period of chilled storage at 4 °C. While a prevalent method for preserving rabbit semen, cryopreservation can elicit cold shock and other stressors, resulting in a decline in sperm quality. Thereafter, the researchers hypothesized that BG, potentially due to its antioxidant properties, could mitigate these detrimental effects. For the experiment, semen samples were diluted in extender and assigned to treatment groups receiving BG at concentrations of 0 (BG0), 100 (BG100), 200 (BG200), or 400 (BG400) µL/mL, followed by storage at 4 °C. Sperm quality parameters (motility, viability, membrane integrity, and morphology) were assessed at 24-, 48-, and 72-hour time points of storage. Results indicated a quadratic improvement in sperm motility, viability, and membrane integrity with the addition of 100 or 200 µL/mL of BG across all time points (P < 0.01). A quadratic relationship was observed between BG supplementation levels and the concentrations of GPx and SOD, indicating a dose-dependent increase. BG treatment at all concentrations led to elevated total antioxidant capacity (TAC) compared to the control, with peak TAC values at 200 and 400 µL/mL BG. Conversely, nitric oxide (NO) levels significantly decreased (P < 0.001) with increasing BG dosage. BG treatment significantly decreased malondialdehyde, H₂O₂, and protein carbonyl levels compared to the control (P < 0.01). Additionally, succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) activities were significantly and quadratically improved at BG concentrations of 200 and 400 µL/mL relative to the 100 µL/mL concentration. In conclusion, supplementing rabbit semen extenders with BG significantly enhanced sperm quality during 72-hour chilled storage by attenuating oxidative stress, bolstering antioxidant capacity, and promoting mitochondrial enzyme activity. These findings suggest that BG is a promising additive for improving the preservation of chilled rabbit semen, potentially benefiting artificial insemination and rabbit breeding programs.
... PCPA was suspended in mildly alkaline saline with 2% Tween 80 for abdomen injection [36]. Beta-myrcene or diazepam were, respectively, suspended in saline with 2% Tween80 and 2% DMSO. ...
Article
Full-text available
With the increasing prevalence of insomnia-related diseases, the effective treatment of insomnia has become an important health research topic. Lavender (Lavandula angustifolia Mill.) essential oil (LEO) is a commonly used medicine for the treatment of insomnia and neurological disorders. However, neither the active components nor its sedative–hypnotic mechanism have been fully discovered. This study aimed to screen the main active terpenes and discover the possible mechanism of LEO through network pharmacology in the treatment of insomnia-related diseases, as well as to verify our hypothesis in insomnia mice. The results showed that, in LEO’s 15 potential active ingredients, beta-myrcene had strong sedative–hypnotic effects through the serotonergic synaptic pathway according to the network pharmacological prediction. Further, PCPA(DL-4-chlorophenylalanine)-induced insomnia mice were treated with beta-myrcene for one day or seven days. The quiet state of insomnia mice was increased effectively, and the hypnotic effect was enhanced by anaobarbital sodium by prolonging sleep duration, decreasing sleep latency, and increasing the rate of falling asleep. Beta-myrcene reduced the damage to hypothalamic neuron cells induced by PCPA and increased neurotransmitter levels of GABA, 5-HT, and Glu in the serum and hypothalamus of insomnia mice. Meanwhile, beta-myrcene exerted an improvement in insomnia by upregulating relevant genes and protein expression in the serotonergic synaptic pathway. These results support the merit of the sedative–hypnotic activity of LEO. Beta-myrcene, a terpene in LEO, may be the main source of its sedative–hypnotic properties. It may serve as a good potential compound in future clinical studies on coping with insomnia.
Article
Full-text available
Curculigo orchioides Gaertn. a medicinal herb with diverse pharmacological activities has been considered as a wonder crop for people working in the herbal pharmaceuticals. Preliminary screening for the presence of phytochemicals in rhizome and leaf extracts of C. orchioides was carried out through qualitative tests. GC-MS analysis of methanolic extracts of leaves and rhizome revealed the presence of several compounds and were interpreted based on the reported compounds in NIST-Wiley library. PASS prediction analysis revealed the pharmacological activities of phytoconstituents in the extracts of C. orchioides. In leaf extracts, the compound 2-Myristynoyl pantetheine covered the max peak area of 32.72%. Further in leaf extracts, 4-Acetyloxyimino-6,6-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro benzo [c] thiophene-1 carboxylic acid methyl ester was also found to possess biological role in treatment of Alzheimer's disease, neurodegenerative disease and cognition disorders. In rhizome, the compound 2,7-Diphenyl-1,6-dioxopyridazino [4,5:2',3']pyrrolo[4',5'-d] pyridazine covered maximum peak area (18.36%) which has predicted biological activity as an antiepileptic, for treating renal disease, heart failure and Alzheimer's disease.
Article
Full-text available
Chronic insomnia disorder is one of the most common problems in postmenopausal women, exacerbated by underdiagnosis and improper treatment. This double-blinded, randomized, placebo-controlled trial was conducted to evaluate the potential of vitamin E to treat chronic insomnia as an alternative to sedative drugs and hormonal therapy. The study enrolled 160 postmenopausal women with chronic insomnia disorder, divided randomly into two groups. The vitamin E group received 400 units of mixed tocopherol daily, while the placebo group received an identical oral capsule. The primary outcome of this study was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI), a self-evaluated and standardized questionnaire. The secondary outcome was the percentage of participants using sedative drugs. There were no significant differences in baseline characteristics between the study groups. However, the median PSQI score at baseline was slightly higher in the vitamin E group compared with the placebo (13 (6, 20) vs. 11 (6, 20); p-value 0.019). After one month of intervention, the PSQI score was significantly lower (indicating better sleep quality) in the vitamin E group compared with the placebo (6 (1, 18) vs. 9 (1, 19); p-value 0.012). Moreover, the improvement score was significantly higher in the vitamin E group compared with the placebo (5 (−6, 14) vs. 1 (−5,13); p-value < 0.001). In addition, there was a significant reduction in the percentage of patients using sedative drugs in the vitamin E group (15%; p-value 0.009), while this reduction was not statistically significant in the placebo group (7.5%; p-value 0.077). This study demonstrates vitamin E’s potential as an excellent alternative treatment for chronic insomnia disorder that improves sleep quality and reduces sedative drug use.
Article
Full-text available
Medicinal plants have played an essential role in the treatment of various diseases. Thymus vulgaris, a medicinal plant, has been extensively used for biological and pharmaceutical potential. The current study was performed to check the biopotential of active biological compounds. The GC-MS analysis identified 31 compounds in methanolic crude extract, among which thymol, carvacrol, p-cymene, and eugenol are the main phytoconstituents present in T. vulgaris. The HPLC analysis quantified that flavonoids and phenolic acids are present in a good concentration in the active fraction of ethyl acetate and n-butanol. FTIR confirmed the presence of functional groups such as phenols, a carboxylic group, hydroxy group, alcohols, and a benzene ring. Among both fractions, ethyl acetate showed high antioxidant activity in the DPPH (84.1 0.88) and ABTS (87.1 0.89) assays, respectively. The anti-inflammatory activity of the fractions was done in vitro and in vivo by using a carrageenan-induced paw edema assay, while the hexane-based extract showed high anti-inflammatory activity (57.1 0.54) in a dose-response manner. Furthermore, the lead compound responsible for inhibition in the denaturation of proteins is thymol, which exhibits the highest binding affinity with COX1 (−6.4 KJ/mol) and COX2 (−6.3 KJ/mol) inflammatory proteins. The hepatotoxicity analysis showed that plant-based phytoconstituents are safe to use and have no toxicity, with no necrosis, fibrosis, and vacuolar degeneration, even at a high concentration of 800 mg/kg body weight. Furthermore, the in silico analysis of HPLC phytochemical compounds against gastric cancer genes showed that chlorogenic acid exhibited anticancer activity and showed good drug-designing characteristics. Thrombolysis and hemolysis are the major concerns of individuals suffering from gastric cancer. However, the T. vulgaris fractions showed thrombolysis from 17.6 to 5.4%; similarly, hemolysis ranged from 9.73 to 7.1% at a concentration of 12 mg/mL. The phytoconstituents present in T. vulgaris have the potential for multiple pharmacological applications. This should be further investigated to isolate bioactive compounds that can be used for the treatment of different ailments.
Article
Full-text available
Plants are excellent sources of secondary metabolites that have been used for the treatment of human diseases. The plant Momordica cymbalaria contains different types of phytochemicals like phenols, steroids, flavonoids, alkaloids and tannins. The present investigation was carried out to determine the bioactive compounds present in the different plant parts of Momordica cymbalaria by Gas chromatography-Mass spectroscopy (GC-MS) technique. Chromatograms and bioactive compounds of in vivo leaf, root and in vitro leaf callus methanolic extracts of Momordica cymbalaria are derived by GC-MS technique. 37 compounds were found in leaf methanolic extracts, 20 compounds in vitro leaf callus methanolic extracts and 18 compounds in root methanolic extracts. These are important bioactive compounds n-Hexadecanoic acid, 9-octadecenoic acid methyl ester, Cholesterol, Cholestanol, 5β-cholestane-3α,7α,12α,24α,25-pentol TMS, 1-Heptatriacotanol, Vitamin E, Ethyl iso-allocholate, Stigmasterol, Β-sitosterol, Lupeol, Diethyl Phthalate, Propanoic acid,2-(3-acetoxy-4,4,14-trimethyl and rost-8-en-17-yl), 1H-pyrrole-2,5,dihydro-1-nitroso, d-Mannose, Spirost-8-en-11-one,3-hydroxy, (3β,5α,14 β,20β,22 β,25R) these are determined from in vivo leaf, root and in vitro callus explants. These identified compounds possess biological activities which can act against the incurable human diseases.
Article
Full-text available
Context Lilium davidii var. unicolour Cotton (Lilium genus, Liliaceae) is an edible plant and a herb used in China to alleviate insomnia. Objective To investigate the alleviating insomnia mechanism of L. davidii (LD). Materials and methods Wistar rats were intraperitoneally injected with p-chlorophenylalanine (PCPA) to establish an insomnia model. Rats were divided into six groups (n = 8): Control, PCPA, Estazolam (0.5 mg/kg), LD extract in low, medium and high doses (185.22, 370.44, 740.88 mg/kg). Serum hormone levels of the HPA axis, levels of 5-HT, NE and MT, and the expression of GABAA and 5-HT1A receptors in hypothalamus were determined. Moreover, behavioural and pathological changes in the hypothalamus were evaluated. Results After LD administration, body weight and brain coefficient increased by 2.74% and 8.22%, respectively, and the adrenal coefficient decreased by 25%, compared with PCPA group. Elevation of the serum hypothalamic-pituitary-adrenal (HPA) axis hormone CRH (11.24 ± 3.16 ng/mL), ACTH (565.87 ± 103.44 pg/mL) and CORT (44.28 ± 8.73 ng/mL) in the PCPA group was reversed after LD treatment. Furthermore, abnormal excitatory behaviour [5 min movement distance (2096.34 ± 259.51 cm), central exercise time (5.28 ± 1.08 s)] of insomnia rats in the PCPA group was also relieved. LD extract increased 5-HT and MT levels, reduced NE level in the hypothalamus, and upregulated the expression of GABAA R and 5-HT1A. Moreover, LD extract may improve the pathology of neurons in the hypothalamus. Conclusions LD can be considered to develop health-care food or novel drugs to cope with the increasing number of insomniacs.
Article
Full-text available
Background: Tumor necrosis factor-α (TNF-α) has been reported to play a part in the development of obstructive sleep apnea (OSA) and its complications. However, the relationship between TNF-α and OSA still remains inconclusive. We aimed to systematically review and synthesize studies published to date on association between the two in adults. Methods: We searched for English-language articles containing original human data from case-control study studies in adults≥18 years of age. The selection criteria were set according to the PICOS framework. Articles were independently reviewed by three investigators. Data regarding demographics, clinical characteristics, and TNF-α levels were obtained. A random-effects model was applied to evaluate the overall effect sizes by calculating standard mean difference (SMD) and its 95% confidence intervals (CIs). Results: Of 393 identified abstracts, 50 articles (3503 OSA patients and 3379 health controls) were ultimately included in this meta-analysis. The results indicated that the TNF-α level in patients with OSA was 1.77 (95%CI, 1.37 to 2.17, I2 = 97.8%, P < 0.0001) times higher than in the control group. Subgroup analyses showed a positive correlation between the level of TNF-α and OSA severity. According to meta-regression, we noted that aging significantly predicted an increased effect size of TNF-α level in OSA patients (P < 0.007). Conclusion: This study identified a significant association between OSA and elevated TNF-α level in adults. Meanwhile, TNF-α levels were consistently correlated with severity of OSA, which indicated it might be a promising biomarker for the development of OSA. However, well-designed, large-scale, case-control cohorts are needed to better understand the relationship of TNF-α in the context of adult OSA.
Article
Full-text available
Introduction: Many atopic dermatitis (AD) patients suffer from insomnia. Out of numerous factors associated with sleep disorders, melatonin seems to play a significant role. Aim: To assess the relation between melatonin concentration and sleep disorders in adult patients with severe and very severe AD. Material and methods: The study included 36 adult patients with severe and very severe AD and 20 healthy Caucasian volunteers. The severity of skin lesions was assessed by the EASI scale. Skin itch was evaluated by a visual-analogue scale (VAS), and sleep disorders were assessed by the Polish version of the Athens Insomnia Scale (AIS). Serum melatonin concentration of patients and controls was determined by ELISA. Results: Melatonin concentration in patients with very severe AD was significantly (p < 0.001) lower than in patients with severe AD, however, melatonin concentration in the group of AD patients did not differ significantly (p = 0.33) from that observed in the control group. There was a significant negative correlation between the concentration of melatonin in the study group and the severity of itching (R = -0.54, p < 0.001). The intensity of sleep disorders was significantly higher (p < 0.001) in patients with a very severe form of AD compared to patients with severe AD. Moreover, there was a significant negative correlation between melatonin concentration and sleep disorders (R = -0.67, p < 0.001). Conclusions: Our results clearly showed that sleep disturbances are more expressed in very severe AD patients compared to subjects suffering from severe disease. We also suggest that melatonin serum concentration could play a role in the pathogenesis of sleep disturbances in AD patients.
Article
The phytochemicals have antioxidant properties to counter the deleterious effects of oxidative stress in the central nervous system and can be a promising drug candidate for neurodegenerative diseases. Among various phytochemicals, recently, constituents of spice origin have received special attention for neurodegenerative diseases owing to their health benefits, therapeutic potential, edible nature, and dietary accessibility and availability. Carvacrol, a phenolic monoterpenoid, has garnered attention in the treatment and management of various human diseases. It possesses diverse pharmacological effects including antioxidant, anti-inflammatory, antimicrobial and anticancer. Alzheimer's disease (AD) and Parkinson's disease (PD) are major public health concerns that place a significant financial burden on healthcare systems worldwide. The global burden of these diseases is expected to increase in the next few decades owing to increasing life expectancies. Currently, there is no cure for neurodegenerative diseases such as, AD and PD, and the available drugs only give symptomatic relief. For a long time, oxidative stress has been recognized as a primary contributor to neurodegeneration. Carvacrol enhances memory and cognition via modulating the effects of oxidative stress, inflammation, and Aβ25-35-induced neurotoxicity in AD. Moreover, it also reduces the production of reactive oxygen species and proinflammatory cytokine levels in PD, which further prevent the loss of dopaminergic neurons in the substantia nigra and improves motor functions. This review highlights the potential antioxidant and anti-inflammatory properties of carvacrol in the management and treatment of AD and PD.
Article
Background & objective Neurological diseases are becoming a significant problem worldwide, with the elderly at a higher risk of being affected. Several researchers have investigated the neuroprotective effects of Carvacrol (CAR) (5-isopropyl-2-methyl phenol). This review systematically surveys the existing literature on the impact of CAR when used as a neuroprotective agent in neurological diseases. Methods The systematic review involved English articles published in the last ten years obtained from PubMed, Google Scholar, and Scopus databases. The following descriptors were used to search the literature: “Carvacrol” [Title] AND “neuroprotective (neuroprotection)” [Title] OR “stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, seizure, epilepsy [Title]. Results : A total of 208 articles were retrieved during the search process, but only 20 studies met the eligibility criteria and were included for review. A total of 20 articles were identified, in which the efficacy of CAR was described in experimental models of stroke, traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, , epilepsy, and seizure, through motor deficits improvements in neurochemical activity, especially antioxidant systems, reducing inflammation, oxidative stress and apoptosis as well as inhibition of TRPC1 and TRPM7. Conclusion The data presented in this study support the beneficial impact of CAR on behavioural and neurochemical deficits. CAR benefits accrue because of its anti-apoptotic, antioxidant, and anti-inflammatory properties. Therefore, CAR has emerged as an alternative treatment for neurological disorders based on its properties.
Article
This study investigated the effect of a dietary supplement containing astaxanthin-rich extract derived from Paracoccus carotinifaciens (astaxanthin supplement) on the status of stress and sleep in individuals aged 20–64 years. Twenty-five subjects orally administered 12 mg astaxanthin/day of astaxanthin supplement for 8 weeks (astaxanthin group) and 29 subjects given a placebo (placebo group) were evaluated with Profile of Mood States 2nd Edition for stress and Oguri–Shirakawa–Azumi Sleep Inventory for Middle-aged and Aged version for sleep. We did not observe any significant intergroup differences in the stress and sleep. A subgroup analysis was performed after dividing the subjects into two groups: those who scored >65 and those who scored ≤65 in the ”Depression–Dejection” dimension of Profile of Mood States 2nd Edition. The sleep of subjects who scored >65 (”Depression–Dejection”) showed significant improvement in the astaxanthin group compared with the placebo group, whereas no significant improvement was observed in stress and the other subjects. Our results indicate that people who tend to be strongly depressed may experience improved sleep after ingesting astaxanthin supplement. On the basis of the parameters tested, administration of astaxanthin supplement was not associated with any problems related to safety. Clinical registration: This study has been registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000038619) on August 24, 2018 as ”A study to evaluate the effect of intake of astaxanthin on the status of stress and sleep in adults,” Identification No. UMIN000033863.