Journal of the Maharaja Sayajirao University of Baroda ISSN : 0025-0422

SIGNIFICANT BREAKTHROUGH IN THE FIELD OF ANTICONVULSANT

NATURAL REMEDIES

Sudhir Kumar, Saras College of Pharmacy, Baghpat, sudhir164@gmail.com

Gaurav Saxena, HIMT College of Pharmacy, Greater Noida
Anjali Sudha, HIMT College of Pharmacy, Greater Noida

ABSTRACT
Epilepsy, which comprises a large array of neurological abnormalities and responsible for almost one
percent of the global burden of chronic disease directly affecting individuals of different ages, is
regarded as an "Apasmara" in the Indian traditional system of medicine widely known as Ayurveda.
The limited availability, high prices, low potency, and adverse events of anti-epileptic drugs (AEDs)
are all critical challenge. Herbal medicine has classically been aspect of epilepsy therapy, is generally
safe, with minimal side effects. To showcase some natural herbs which have been evaluated in
preclinical studies for their antiepileptic efficacy, a review of literature via PubMed as well as Science
Direct was therefore pursued. The studies basically consisted of phenotypic model tests, with really
no uniqueness of screening tools. In some studies, the extracts tested prolonged the time to onset of
epileptic fits and decreased the span of seizures. Most investigators imply potentiation of GABAergic
activity as the mechanism of action of the extract, even if some researchers haven't yet entirely
established the bioactive molecular structure of the crude extract.
Keywords: Neuron, drug, epilepsy, herbal medicine, GABA, Brain.

INTRODUCTION
Epilepsy (EP) is among the earliest recognised neurological disorders worldwide, with quite a history
of 4,000 BC of misconception, unawareness, and degradation of the sufferers. 1 Epilepsy is typified as
recurring unprovoked seizures prompted by severe and irregular cortical neural brain activity. The
epilepsy occurrence is accompanied by convulsive or non-convulsive fits. 2, 3 This neurological
disorder has been one of the most researched medical condition mainly due to the complex morbidity
associations with substantially high mortality rates. 4,5 In the context of infants, the likelihood of
fatalities is significantly higher relative to the public. For childhood -onset epilepsy, complex
relationships between intrinsic epileptic co-morbidities in the developing young brain remain a
significant medical concern.6
EP is a progressive neuronal neurodegenerative disorder caused by repeated and involuntary fits
(epileptogenic convulsions) resulting to irregular shaking of the body or body parts. Medical
symptoms of epileptic seizures are recognised as synchronous neuronal activation within brain. 7
Almost all antiepileptic prescription drugs (AEDs) don't really suppress or counteract the physiological
pathway driving epilepsy and therefore aggressively pursuing alternative treatments with fewer
adverse effects and greater effectiveness is required. 8 In addition, 30-40% of individuals exhibit
resilient or intransigent epilepsy. 9
While natural remedies are efficacious and benign in virtue and are among the most popular ones of
complementary and alternative medicines (CAMs), the use in the treatment of neuro brain disorders is

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already receiving attention. Medicinal herbs preparations exhibit its poly-pharmacological influence
using its multi-component matrix to operate on multiple targets. 10 EP is classified as Apasmara by
Ayurvedic system of medicine, apa refers to "refutation" and smara as "cognition".11
For the management of psychiatric conditions including migraine, epilepsy, Alzheimer's, anxiety,
Parkinson's, depression and so on., Ayurveda goes on to describe the use of selected species and plant-
based preparations.12-14. The goal of this analysis is to showcase latest events in herbal treatment for
epilepsy. Accordingly, we initially documented the prevalently employed anti-epileptic plants of
Ayurveda in present study and afterwards the poly-pharmacological appraisal was done out using the
network pharmacology strategy. For this reason, we scrutinised and categorized the anti-epileptic
herbs of Ayurveda from major scientific assets.

2. Material and Methods

A literature review was conducted using various online resources including PubMed and Science
Direct to structure this review.

Identification of anti-epileptic herbs (AEHs) and drugs (AEDs).

To collect the information of the anti-EP herbs prescribed in Ayurveda system of medicine, pertinent
research articles in PubMed-NCBI (https:// www.ncbi.nlm.nih.gov/pubmed/) were shortlisted and
manually inspected. For the identification of the AEDs that are in current use and also under clinical
trials, DrugBank database (https://www.drugbank.ca/) 15 screening and literature survey were
performed.16

Phytochemical dataset preparation of anti-epileptic herbs.

A list of phytochemicals present in the identified Anti-epileptic herbs was compiled from 3 database
sources: Duke’s phytochemical database (https:// phytochem.nal.usda.gov/phytochem/search), 17, and
PCIDB (PhytoChemical Interactions DB) (https://www.genome.jp/db/pcidb). PubChem
(https://pubchemncbi.nlm.nih.gov/) and ChEMBL (https://www.ebi.ac.uk/chembl/) databases of
chemical compounds were used to derive the chemical information of phytochemicals. 2D and 3D
chemical structures of phytochemicals were obtained using OpenBabel 2.4.1 software 18. The
phytochemicals, for which no chemical information could be obtained, were not considered in this
study.

Protein target identification of AEDs and phytochemicals in AEHs (phytochemical dataset).

Identification of potential drug targets is considered a key step towards the drug development
procedure 19,20. Here, three target prediction software’s were used to collect the information of potential
protein targets of the phytochemical dataset.
(1) BindingDB (https://www.bindingdb.org/), a web-accessible public database that contains the
protein interaction information of the potential drug targets with their ligand molecules 21 For accessing
the high confidence interaction pairs, BindingDB was searched with interaction score of ≥0.85.

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(2) STITCH 5.0 (http://stitch.embl.de/), which catalogues the information of manually curated as well
as experimentally validated protein-chemical interactions 22 Only the chemical interactions with
STITCH confidence score of ≥0.4 were considered.
(3) Swiss Target Prediction (http://www.swisstargetprediction.ch/), a web server for the target
identification of bioactive small molecules that uses the combination of 2D and 3D similarity measures
for the prediction of top-15 targets 23 For all the predictions, search was limited to “Homo sapiens”.
EP targets (EP-gene pool).
The data of EP associated genes were collected from three databases: (1) EpilepsyGene
(http://www.wzgenomics.cn/EpilepsyGene/), a genetic resource which accounts for the information
on epilepsy-related genes and mutations, collected from various research publications. 24
(2) OMIM database (http://omim.org/), a frequently updated catalogue of human genes, genetic
phenotypes and traits for establishing a relationship between phenotype and genotype;
(3) DisGeNET, a collection of disease-associated genes and variants associated with Homo sapiens 25
Table 1. Effects of herbal extracts tested for anticonvulsant activity in animal models. 18
Herb Experimental model Effect/ Results
Cannabis Mouse PTZ-induced clonic ACEA administered i.p (10 mg/kg) with PMSF
sativa seizure. (30 mg/kg) significantly enhanced the
anticonvulsant activity of ethosuximide,
phenobarbital, and valproate but not
clonazepam. This treatment also increased the
free plasma and total brain concentration of
ethosuximide and valproate, but not clonazepam
and phenobarbital.
Morus alba Isonicotinic hydrazide (INH) and Isolated morusin injection (i.p) ameliorated the
maximal electroshock (MES) in epileptic seizure. It increased the latency to onset
Wister albino rats of seizure and decreased the duration of
convulsions, with no mortality was recorded. At
5 mg/kg and 10 mg/kg dose, Morusin exhibited
significant reduction and total absence in tonic
hind limb extension (THLE) respectively
Berberis PTZ-induced seizures in mice Hydromethanolic and chloroform fractions of
integerrima the extract increased the onset time of HLTEs
compared to the negative control group.
However, the extracts did not show any positive
effect on reduction of HLTE duration, indicating
absence of protective effect on protective
activity against grand mal epilepsy. Moreover, it
did not show significant protection against
mortality.
Withania Pilocarpine induced epilepsy in All animals injected with pilocarpine developed
somnifera male Wister rats status epilepticus within 20 to 40 minutes.

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Treatment using Withania somnifera extract and

Withanolide A significantly reversed the
increased cerebellum glutamate content
associated with epilepsy, well comparable to the
effect of carbamazepine.
Mondia Pilocarpine induced seizure Methanol extract, ethyl acetate and hexane
whitei fractions at 25, 50 and 100mg/kg exhibited
delayed seizure onset and reduced the duration in
a dose dependent manner. Although it did not
prevent the seizures, it protected the rats from
mortality and exhibited partial recovery
Viscum Swiss albino mice and Wister Pretreatment with the extract reduced the phases
album albino rats of either sex in the of the various epileptic seizures and increased
PTZ- induced seizure model the latency to the first convulsion. The extract
also reduced the locomotor activity, as does
other AEDs, though less than diazepam.
Morus alba Isonicotinic hydrazide (INH) and Isolated morusin injection (i.p) ameliorated the
maximal electroshock (MES) in epileptic seizure. It increased the latency to onset
Wister albino rats of seizure and decreased the duration of
convulsions, with no mortality was recorded. At
5 mg/kg and 10 mg/kg dose, Morusin exhibited
significant reduction and total absence in tonic
hind limb extension (THLE) respectively

4. DISCUSSION: Herbal medicines generally have a broad spectrum because they are an assortment
of bioactive compounds. Although herbs have been used for years and tested in animal trials, there is
a lack of standardization and safety and efficacy studies, restricting their utilization in modern
medicine 26 For a substance to be an effective anticonvulsant, it must cross the blood-brain barrier.
Selecting the appropriate model is a key factor in AED screening in the case of false positive or false-
negative results 27 as different models could simulate dissimilar kinds of epilepsy. Maximal
electroshock (MES) and subcutaneous pentylenetetrazol (PTZ) are the two most widely used models
in screening compounds for antiepileptic activity. Novel potential targets for the treatment of epilepsy
have been described 28. Time is riper now than never before for the diversification and adoption of
more screening animal models. Besides, testing a substance in different models gives a more holistic
idea of the substance’s efficacy as each model models a different form of epilepsy and thus a different
mechanism of action of the test extract. It is evident that herbal extracts have potential to be a rich
source for safer and more effective, low-cost and culturally acceptable antiepileptic agents especially
in resource poor regions. In most experiments, the tested extracts pro-longed the time to onset of
seizures and decreased their duration. The mode of administration was either intraperitoneal or oral,
and where it was recorded, the toxicity was nonlethal up to a dosage of 2000mg/kg. The two most
important neurotransmitters involved in the regulation of brain neuronal activity are the excitatory

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neurotransmitter glutamate and the inhibitory neurotransmitter GABA. The most widely understood
mechanism of action of AEDs include modulation of voltage-gated cation channels, potentiation of
GABA-ergic activity and inhibition of glutamatergic processes. Substances that are effective against
PTZ induced seizures are thought to act on GABA transmission while those effective against the MES
model are considered to block sodium channels. Majority of experimenters have focused on substances
whose mode of action involve these neurotransmitters, particularly the inhibition of enzymes involved
in the degradation of GABA, as seen from the wide use of PTZ seizure induced model 29. We are ready
for the diversification and adoption of more screening animal models. Besides, testing a substance in
different models gives a more holistic idea of the substance’s efficacy as each model models a different
form of epilepsy and thus a different mechanism of action of the test extract. It is evident that herbal
extracts have potential to be a rich source for safer and more effective, low-cost, and culturally
acceptable antiepileptic agents especially in poor regions. In most experiments, the tested extracts pro-
longed the time to onset of seizures and decreased their duration. The mode of administration was
either intraperitoneal or oral, and where it was recorded, the toxicity was nonlethal up to a dosage of
2000mg/kg. Most importantly, some extracts were able to completely prevent the experimentally
induced seizures at non-lethal doses 30 or from death caused by induced seizure 31-33 while others
worked only in combination, as adjuvants, offering additive or synergistic effects with conventional
AEDs. This is an important aspect to bear in mind as it holds the potential to reduce the dosage of the
conventional AEDs when used in combination with herbal extracts. This would in turn reduce the
current problem of side effects caused by conventional AEDs. while others worked only in
combination, as adjuvants, offering additive or synergistic effects with conventional AEDs. This is an
important aspect to bear in mind as it holds the potential to reduce the dosage of the conventional
AEDs when used in combination with herbal extracts. This would in turn reduce the current problem
of side effects caused by conventional AEDs.
CONCLUSION: The limited efficacy of AEDs is still a matter of concern. Animal models have been
used since time immemorial to test new drugs and are continually becoming more sophisticated as
technology and scientific understanding progresses. This review has presented some of the potential
herbal remedies that have been tested and shown positive results in animal models. It remains unclear
how many of such potential remedies actually make it into clinical trials and eventually making part
of the AED list. More research in this area, applying strict research methodology with uniform herbal
combinations, as well as clinical studies with selected standardized botanical extracts are urgently
needed to determine which is most efficacious 34,35. Rigorous pre-clinical and clinical studies are
encouraged to help the legacy of herbal medicine gain more impact and recognition.

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