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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 2  |  Page : 158-164

Evaluation of anticonvulsant activity of polyherbal formulation based on ayurvedic formulation Brihad Panchagavya Ghrita


Department of Ayurveda Pharmacy, Ayurvedic Pharmacy Laboratory, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur, Uttar Pradesh, India

Date of Web Publication29-Sep-2016

Correspondence Address:
Santosh Kumar Maurya
Ayurvedic Pharmacy Laboratory, Rajiv Gandhi South Campus, Banaras Hindu University, Barkachha, Mirzapur - 231 001, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5006.191257

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  Abstract 

Background: The aim of the present study was to develop a polyherbal formulation for epilepsy. Present polyherbal formulation (PHF) (containing Operculina turpethum (L.) Silva Manso, Mimosa pudica L., Uraria picta (Jacq.) DC., Cajanus cajan (L.) Millsp, and Lawsonia inermis L.) is based on an ayurvedic formulation " Brihad Panchagavya Ghrita" indicated for epilepsy.
Materials and Methods: To establish the scientific basis of mechanism, we examined the effects of methanolic extract of PHF (100, 200, and 400 mg/kg, p.o.) on maximal electric shock (MES), pentylenetetrazol (PTZ), and isoniazid (INH)-induced convulsions as well as gamma-aminobutyric acid (GABA)-glutamate level in the brain tissues in PTZ-induced seizure model. Phenytoin (25 mg/kg, i.p.) for MES-induced seizure and diazepam (2 mg/kg, i.p.) for PTZ and INH-induced epilepsy were used as reference drugs, respectively.
Results: The extract showed no toxicity and significantly prolonged the onset and reduced the duration of the seizures induced by MES. Phenytoin (25 mg/kg, i.p.) completely inhibited the seizures in this model. Similarly, in the seizures induced by PTZ and INH, the extract also prolonged the onset and reduced the duration of the seizures though not in a dose-dependent manner. Diazepam also inhibits the PTZ and INH-induced seizures. The plant extract however showed a significant anticonvulsant activity at 400 mg/kg in comparison with diazepam. The extract also attenuates the chemical (PTZ) induce oxidative stress in the brain. Moreover, the extract (400 mg/kg) also significantly decreases the GABA-transaminase enzyme activity in PTZ model. The PHF was also found to be capable in reversing the INH-induced decline in GABA level and increase in glutamate level in the brain.
Conclusions: The results obtained from this work suggest that PHF has anticonvulsant activity, and this supports the use of the formulation traditionally in the treatment of convulsions.

Keywords: Ayurveda, epilepsy, maximal electric shock, oxidative stress, polyherbal formulation


How to cite this article:
Ghosh A, Mishra A, Seth A, Maurya SK. Evaluation of anticonvulsant activity of polyherbal formulation based on ayurvedic formulation Brihad Panchagavya Ghrita. Indian J Health Sci Biomed Res 2016;9:158-64

How to cite this URL:
Ghosh A, Mishra A, Seth A, Maurya SK. Evaluation of anticonvulsant activity of polyherbal formulation based on ayurvedic formulation Brihad Panchagavya Ghrita. Indian J Health Sci Biomed Res [serial online] 2016 [cited 2022 May 17];9:158-64. Available from: https://www.ijournalhs.org/text.asp?2016/9/2/158/191257


  Introduction Top


Epilepsy is a common neurological disorder which affects around 65 million people worldwide. [1] It may be define as a chronic and dynamic neurological condition of an abnormal, excessive, hypersynchronous discharge of a population of cortical neurons [2] associated with ongoing neuronal damage, particularly when uncontrolled and causes physical, psychological, and social abnormalities in patients. Epilepsy possess very complex pathophysiology involving neuronal plasticity, imbalance between gamma-aminobutyric acidergic (GABAergic) (inhibitory) and glutamatergic (excitatory) neurotransmitter system and ion exchange dysfunction. [3] Thus, a decrease in concentration of gamma-aminobutyric acid (GABA) leads to many pathological processes in the brain which may be manifests into convulsive episodes. [3] Recurrent and spontaneous seizures may enhance reactive oxygen species (ROS) in the central nervous system. [4] Due to the high levels of polyunsaturated fatty acids, high rate of oxidative metabolism and lower levels of antioxidant defenses, the brain is more susceptible to oxidative stress. [5] Although a large number of anticonvulsant agents are present in the market, still a number of cases of drug resistance increases day by day. Available antiepileptic drugs are inadequate and not capable to control seizures in many patients (failure rate 30-40%). [6] Since the treatment duration is very long for epilepsy; therefore, the drugs produce a variety of side effects and other neuropsychological disorders. [7] In addition, these drugs cannot prevent neurodegeneration process and have a negative impact on cognitive abilities and memory. Ninety percent of epileptic patients are from developing countries [8] and approximately three-fourths of them are not receiving adequate treatment. These few factors create interest in researches to find new and effective agents and formulations from natural sources, which are safe in prolonged usage for the management of epilepsy.

Ayurveda has a history of 5000 years in the Health Care in Southeast Asia. The different types of epilepsy are mentioned under one umbrella known as "Apasmara.0" Different approaches have been mentioned in classical texts. Chakradatta is a popular ayurvedic treatment text written by Chakrapanidatta in the 11 th century. Present polyherbal formulation (PHF) (containing Operculina turpethum (L.) Silva Manso, Mimosa pudica L., Uraria picta (Jacq.) DC., Cajanus cajan (L.) Millsp, and Lawsonia inermis L.) is a part of ayurvedic formulation "Brihad Panchagavya Ghrita" indicated for jaundice and epilepsy. [9] Previously, we evaluated the formulation for its hepatoprotective activity and in vivo antioxidant activity in liver tissues. [10] Hence, the present study is undertaken for the anticonvulsant activity of the PHF using maximal electroshock shock (MES), pentylenetetrazole (PTZ), and isoniazid (INH)-induced convulsions in rats.


  Materials and Methods Top


Materials

The plant materials C. cajan (whole plant, 1 part), O. turpethum (root, 2 part), M. pudica (root, 1 part), U. picta (root, 1 part), and L. inermis (leaves, ½ part) were collected from the Rajiv Gandhi South Campus, Banaras Hindu University, Barkachha, Mirzapur, Uttar Pradesh. The specimens were authenticated by Prof. Anil Kumar Singh, Institute of Medical Science, Banaras Hindu University, Varanasi, India. The voucher specimens (APRL/HERB/12-13/112-116) of plant materials were deposited in Rajiv Gandhi South Campus, Banaras Hindu University, Barkachha, Mirzapur (Uttar Pradesh) India, for further reference.

Preparation of formulation

The formulation was prepared as per the method described in the previous studies in our laboratory. [10]

Chemical

NADH and NBT have been procured from Sisco Research Laboratories Pvt. Ltd, Mumbai, PTZ, diazepam, and phenytoin were purchased from Sigma-Aldrich, New Delhi, India. For the estimation of GABA-transaminase (GABA-T) activity, ELISA kit (MBS939900; MyBioSource, Inc., San Diego, CA, USA) was used. All the reagents used in the study were of analytical grade.

Pharmacological evaluation

Animals

In the experimental study, adult Charles Foster albino rats weighing 150 ± 20 g (obtained from Central Animal House, Banaras Hindu University [Registration No. 542/AB/CPCSEA]) were used. The animals were kept at a constant room temperature (22 ± 2°C) and maintained 12 h light and 12 h dark cycle. All the experiments were carried out according to protocol approved by the Institutional Animal Ethical Committee (Dean/13-14/CAEC/318). The animals were fed ad libitum with standard pelleted feed (Amrit Pvt. Ltd. Pune, Maharashtra, India) and fresh water during the course of the study.

In vivo anticonvulsant screening

Maximal electric shock-induced seizures

The electrical stimulus (150 mA, 50 Hz, 0.2 s duration) was applied via ear clip electrodes using an electroconvulsiometer (Techno, India). Five groups (n = 6) of rats were divided as follows. Group I received the vehicle carboxymethyl cellulose (0.5% CMC, p.o.). Group II received standard drug phenytoin (25 mg/kg, i.p.). Group III, IV, and V received different doses (100, 200, and 400 mg/kg, p.o.) of PHF, respectively. Thirty minutes after treatment, electrical stimulation was given to all the animals. Abolition of hind limb tonic extension within 2 min was the criterion in the model. [11]

Pentylenetetrazole -induced seizures

PTZ (70 mg/kg, i.p.) was used after 30 min of vehicle/drug treatment to induce clonic-tonic convulsions in experimental rats. Six groups (n = 6) of rats were divided as follows. Group I received the vehicle (0.5% CMC, p.o.). Group II received only PTZ. Group III received standard drug diazepam (2 mg/kg, i.p.), whereas Group IV, V, and VI received different doses (100, 200, and 400 mg/kg, p.o.) of PHF, respectively. The onset time of clonic-tonic, myoclonus, and tonic seizures has been then recorded. The animals were considered to be protected if no seizure has been observed during the observation period of 30 min. Finally, after 30 min observation, rats were sacrificed by decapitation and the whole brain was dissected out for estimation of GABA-T activity and in vitro antioxidant activity. [12]

Estimation of gamma-aminobutyric acid-transaminase activity

GABA-T activity has been measured in the brain homogenate by ultraviolet/visible spectroscopic analysis [13] at 450 nm using ELISA kit (MBS939900; MyBioSource, Inc., San Diego, CA, USA). GABA-T was estimated as pg/mg of protein. Five hundred milligram of each brain tissue was washed with phosphate buffer (PBS, pH 7.2-7.4) and it was then homogenized in 5.0 ml of PBS which was kept overnight at –20°C. The homogenates were centrifuged at 5000 × g for 5 min at the temperature 2-8°C. The supernatant was separated and evaluated for the estimation of GABA-T activity using the user's manual provided by the company along with the kit and for estimation of oxidant stress markers.

In vivo antioxidant estimation

Various markers for the estimation of antioxidant potential such as lipid peroxidation (LPO), glutathione (GSH), and superoxide dismutase (SOD) has been measured as per the methods mentioned in our previous work, and brain tissue was used instead of liver tissue. [10]

Isoniazid-induced convulsions

Wistar albino rats (150-200 g) were divided into 6 groups (n = 6). Group 1 treated as normal group. Group 2 (positive control) received vehicle, Group 3 received diazepam (2 mg/kg), and Group 4-6 received PHF (100, 200, and 400 mg/kg). Forty-five minutes after administration of vehicle or test drug and 30 min after diazepam, all rats were treated with 300 mg/kg INH by i.p. route. Immediately after INH injection, each rat was kept in a separate cage and observed for the next 2 h to record latency to clonic seizures, durations of convulsions, incidence, and any mortality. If in an animal, convulsion not occur within 30 min, it was considered as full protected. [14]

Determination of gamma-aminobutyric acid and glutamate in brain homogenate

Homogenization of brain tissues was carried out in 0.1 M Perchloric acid containing 4 mM sodium metabisulfite solution (30 μL per 10 mg of tissue). [15] The homogenate was then centrifuged at 10,000 rpm at 4°C for 15 min, and the resultant pellet was then separated from the supernatant. Pellet and filtered supernatant were then stored separately at –80°C. Concentration of GABA and glutamate was estimated using precolumn derivatization with o-phthalaldehyde (OPA) and detection of fluorescence has been done. [16] The procedure of derivatization includes mixing of 20 μL filtered supernatant with 6 μL OPA, and after 2 min, this mixture was then injected into the solvent stream of the HPLC system. OPA-GABA and OPA-glutamate were separated out on a reversed phase 3.9 mm × 150 mm column (nova-pack, 4 μm, C18, waters) using a binary gradient system of mobile Phase A (38.74 mM sodium acetate dissolved in 90% milli-Q water and 10% methanol, pH 5.75;) and mobile Phase B (buffer containing 20% solution A and 80% methanol, pH 6.75) at 35°C at a flow rate of 0.5 mL/min. Fluorometric detection was performed at 360 and 450 nm, respectively, with a fluorescence detector (waters, 474). External standards (Sigma, USA) were used to quantify the GABA and glutamate by linear regression in this method and expressed in term of μg/mg protein.

Statistical analysis

Statistical analysis was performed using GraphPad Prism Software Version 5.01, Inc. Fay Avenue, La Jolla, CA, USA. All data were expressed as a mean ± standard error of the mean. One-way ANOVA followed by the Tukey's multiple comparison tests was used for comparisons of different groups of animals. Values of P < 0.05 were considered statistically significant.


  Results and Discussion Top


The aim of the present work was to explore the protective role of PHF against convulsion induced by physical (MES) and chemical (PTZ and INH) injury in experimental rats [Figure 1]. This study provided evidence that PHF is capable of blocking generalized seizures induced by MES test in treated rats. Inhibition of inducible MES seizures by a PHF might support the continuation of the traditional use of this formulation in the convulsive disorders [Figure 2]. Moreover, PHF also attenuated the PTZ and NIH-induced increase in the activity of GABA-T, GABA, and glutamate level of LPO and decrease in GSH and SOD levels in the rat brain [Table 1], [Table 2] and [Figure 3] [Figure 4] [Figure 5].
Figure 1: Graphical abstract


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Figure 2: Effect of polyherbal formulation on MES-induced convulsion. Values are expressed as mean ± standard error of the mean ( n = 6). Statistical comparison was analyzed by one-way ANOVA followed by Tukey's multiple comparison test. a P <</i> 0.05, statistically significant as compared to negative control; b p <</i> 0.05, statistically significant as compared to phenytoin (25 mg/kg, i.p.)


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Figure 3: Effect of polyherbal formulation on oxidative markers in pentylenetetrazol-induced convulsion in rats. Values are expressed as mean ± standard error of the mean (n0 = 6). Statistical comparison was analyzed by one-way ANOVA followed by Tukey's multiple comparison test. aP <</i> 0.05, statistically significant as compared to negative control; bP < 0.05, statistically significant as compared to diazepam (2 mg/kg, i.p.)


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Figure 4: Effect of polyherbal formulation on gamma-aminobutyric acid-transaminase activity in the brain in pentylenetetrazol-induced convulsion in rats. Values are expressed as mean ± standard error of the mean (n0 = 6). Statistical comparison was analyzed by one-way ANOVA followed by Tukey's multiple comparison test. aP <</i> 0.05, statistically significant as compared to negative control; bP < 0.05, statistically significant as compared to diazepam (2 mg/kg, i.p.)


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Figure 5: Effect of polyherbal formulation on isoniazid-induced seizures gamma amino butyric acid and glutamate level in brain homogenate. Values are expressed as mean ± standard error of the mean (n0 = 6). Statistical comparison was analyzed by one-way ANOVA followed by Tukey's multiple comparison test. aP <</i> 0.05, statistically significant as compared to negative control; bP < 0.05, statistically significant as compared to diazepam (2 mg/kg, i.p.)


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Table 1: Effect of present polyherbal formulation on pentylenetetrazole-induced seizures


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Table 2: Effect of present polyherbal formulation on isoniazid-induced seizures


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Maximal electric shock (MES) and PTZ are most commonly used to produce acute seizure in experimental animals. [17] Electroshock produces generalized electrical stimulation of the large portions of the brain; it provokes the neurons to fire repetitively, which is the characteristic of epileptic neurons. Drugs effective in MES model are considered as possible antiepileptic agent against generalized tonic-clonic (grand mal) seizures. [17] The drugs with inhibitory effect on MES convulsions might act with different mechanisms. For example, seizures in MES model were mainly due to the propagation of stimulus all over the body. Anticonvulsant drugs that inhibit MES-induced convulsions acts by blocking the seizure spread, for example, phenytoin primarily acts by blocking voltage-dependent Na + channels. [18] The present results show that phenytoin and PHF were not capable in preventing seizures in animal completely. However, the test drug reduces duration of tonic convulsion significantly showing its ability to slow down the spread of seizure. Hence, results were in agreement with ethnomedicinal use of the drug in grand mal epilepsy.

PTZ, a GABA A receptor antagonist, induced seizures is a well-established animal model to assess efficacy of drugs capable in preventing generalized absence seizures. [17] In laboratory animals, PTZ administration induces a continuum of behavioral response starting from small myoclonic twitches, clonic seizures, and threshold tonic extensor or supramaximal tonic extensor. [19] It can be reasonably accepted that screening by the s.c./i.p. PTZ test is preferred for those compounds which increase GABAergic neurotransmission or which act by affecting T-type calcium (Ca 2+ ) channels, for example, phenobarbital, diazepam, and tiagabine. [20] A catabolic enzyme GABA-T is responsible for depletion in the level of GABA in mammalian brain as it catalyzes the reaction of GABA and α-ketoglutarate to give glutamate and succinic semialdehyde. [21] GABA-T activity rises significantly in PTZ-treated rats, whereas pretreatment with PHF (200-400 mg/kg, p.o.) attenuated the enzyme activity. Production of oxidative stress and imbalance between GABA and glutamate are key features of convulsion. [4] Therefore, estimation of GABA was also carried out in the PTZ-treated rats. The PHF was found to be capable of preventing depletion of GABA in the rat brain caused by PTZ. Oxidative stress produced in rat brain was characterized by increase in the activity of LPO and reduction in the activity of SOD and GSH. [22] PHF reversed this oxidative stress situation successfully and reduced generation of ROS in convulsive rats. The potent effect of diazepam as evident in the PTZ-induced convulsions agrees with its enhancing effects in GABAergic neurotransmission. The extract shows comparable activity with that of diazepam in PTZ test which may suggests the involvement of GABAergic pathway.

INH is a well-known antitubercular drug, but the drug is also known for its effect on GABA-synthesis inhibitor, glutamic acid decarboxylase. [23],[24] The inhibitory effect of INH on the enzyme leads depletion of GABA concentration [25] and increase in glutamate level in the brain. Depletion of GABA concentration resulted in seizure. PHF increases the incidence of first clonic convulsion and moderate effect on the GABA synthesis mechanism in rats. The results suggest that the possible mechanism of PHF effect was either prevention of the decrease in GABA or modification of the rate of GABA depletion produced by INH. [26],[27]

In traditional Chinese medicine, C. cajan has been reported for its use to relieve pain and as sedative. [28] Pinostrobin (5-hydroxy-7-methoxy-2-phenyl-chroman-4-one) is a substituted flavanone from C. cajan on was reported for VGSC-dependent depolarization of synaptoneurosomes isolated from mouse brain. [29] The decoction of M. pudica has been reported to antagonize chemical-induced seizures in mice. Antagonism of PTZ-induced seizures suggests that the extract of M. pudica might have effects on GABA-mediated neurotransmission. [30]

Previously, we have reported that the PHF extract contains polyphenols and phenolic compounds. [10] It has been already shown that some polyphenols are able to bind inhibitory GABA sites, increase GABAergic activity and show an anticonvulsant effect in animal models of epilepsy. [31] Polyphenols were reported to be useful in reducing oxidative neuronal death and preventing neurodegenerative diseases in animal models. [32] Phenolic compounds can prevent the generation of ROS by chelating trace elements involved in radical production, scavenging reactive species, and regulating or protecting antioxidant defenses. [33] However, it is known that polyphenols uptake into the brain of animals are limited. Based on this knowledge, other possible explanations for polyphenols effects could be their ability to act on the neurotransmitter reuptake mechanisms and on cellular signaling pathways. Several phytochemicals such as flavonoids have been reported for anticonvulsant activity in various models such as PTZ and MES. For example, apigenin which tightly binds to benzodiazepine (BZD) receptors or chrysin is a ligand for the BZD receptors. [34] The PHF may exert its effect because of the agonist effects of flavonoids on BZD receptors.


  Conclusions Top


Based on our results of in vivo experimentation, it can be suggested that the present formulation possess and anticonvulsant property; possibly mediated through positive modulation of GABA. The results partially support the use of the present formulation in the management of epilepsy. Multiple phytoconstituents were may responsible for the observed neuropharmacological actions of the PHF. Therefore, further studies need to identify the specific phytomolecules and their particular mechanism(s) of action.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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