1. INTRODUCTION:

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures.^[1] Seizures are episodes of disturbed brain activity that cause changes in attention or behaviour.^[2] The incidence of epilepsy has been reported 5-10 cases per 1000 persons and it affects approximately 1% of the world’s population.^[3,4] Epilepsy has significant economic implications in terms of premature death, health care needs and lost work productivity. The ideal anti-seizure drug is supposed to suppress all seizures without causing any untoward effect. Unlikely these drugs also frequently cause side effects.

In addition to adverse effects, other important parameter like safety, tolerability, efficiency, expenses especially in long term therapy, serum drug monitoring etc. are other limitations with synthetic antiepileptic drugs.^[2] In this regard medicines from Ayurved science can provide a concrete solution in terms of cost effectiveness, improvement of patient compliance and with least side effects.

In Ayurvedic texts, Apasmar (~Epilepsy) is defined as sudden abhorrent bodily activities accompanied by momentary blackouts or loss of consciousness owing to disturbance in mental faculties like dhi (~ grasping power), dhruti (~retention) and smruti (~memory).^[2] Approximately 112 formulations are documented in Ayurvedic classical texts for the treatment of Apasmar. Among them Siddha Ghrita i.e. medicated ghee is the most frequently recommended dosage form. When ghee is processed with medicinal herbs it potentiates their activity and utility many folds.

In the preparation of Sneha paka (medicated ghee/oil), particular drugs and liquid media like juice or decoction, are taken in specific ratio and heated along with oil/ghee at a very specific temperature with certain duration till the completion test. Here, the principle is to transfer active constituents of herbs in lipid and water according to solubility.^[5]Sneha if taken internally enters the systemic circulation and thereby stimulates the central nervous system. Lipid soluble active principles can easily cross the blood brain barrier. Thus Amalakyadi Ghrita containing active principles of the ingredients can easily cross blood brain barrier delivering those at the specific sites of their action. ^{[6, 7]}

Amalakyadi Ghrita [AG] is a formulation recommended in the treatment of Apasmar in Charak Samhita.^[8] AG contains Amalaki Swaras (Emblica officinalis), Yashtimadhu Kalka (Glycyrrhiza glabra) and Goghrita. The ingredients are easily available. Amalaki has Vrushya (~aphrodisiac), Rasayana (~rejuvenation), Medhya (~intellect promoting) and Vayasthapana (~antiaging) activities.^{[9, 10]}It also enhances sense of perception and vitality and increases learning capacity and memory of an individual.^[11] Yashtimadhu possesses Medhya, Vrushya, Balya (~imparts strength), Rasayana, Jivaniya (~life promotive), Vedanasthapana (Analgesic) and Apasmar nashak (antiepileptic property) activities ^[12] and Goghrita possesses Smruti, Buddhi, Agnivardhak, Unmadnashak (~useful in treatment of insanity), Apasmarnashak (~useful in treatment epilepsy) and Murchhanashak (~useful in treatment catalepsy) activities.^[13] All the three drugs Amalaki, Yashtimadhu and Goghrita possess Medhya activity. Hence synergic effect of these three contents makes the drug more potent and useful in the treatment of Apasmar.

2. MATERIAL AND METHODS:

2.1 Material

A. Test Drug:

Amalakyadi Ghrita contains 3 ingredients as shown in Table 1.

Table 1: Ingredients of Amalakyadi Ghrita

Drug Name and part used	Botanical Name/ English Name	Form used	Ratio
Yashtimadhu (Dry roots)	Glycyrrhiza glabra	Kalka (Fine paste)	1part
Goghrita	Cow ghee	--	8 parts
Amalaki (Fresh fruits)	Emblica officinalis	Swaras (Self expressed juice)	128 parts

B. Control Drug:

Cow ghee obtained from the mentioned source (Kenjal, Wai) was used as the control drug

C. Standard Drug:

Phenytoin Sodium (Abbott India) and Sodium Valproate (Sun Pharma) were used as Positive Control drugs in MES and PTZ models respectively.

Chemicals: Pentylenetetrazole (PTZ) (Sigma – Aldrich Mfg.) was used as a chemical convulsant in PTZ model.

D. Animals:

All activities were carried out as per CPCSEA norms after obtaining the approval (BVDUMC/443/2012-13) from Institutional Animal Ethical Committee.

Adult male Swiss albino mice of either sex weighing 18-30gm., eight animals per group were used for MES and PTZ study respectively. The animals were housed in standard cages at 24-27^oc on a12/12h light dark cycle. They were supplied with standard food and water ad libitum

2.2 Methodology:

· Collection, Identification and Authentication of Ingredients:

Fresh Amalaki fruits, Dry roots of yashtimadhu were collected, identified using Ayurvedic Pharmacopoeia of India (API) parameters and then authenticated. Cow ghee was obtained from an authentic source found at small village Kenjal (Wai), District Satara, State Maharasthra where Gir breed cows are reared using natural environment and food. Ghee is prepared by traditional desi method.

· AG Preparation:

Amalaki swaras^[14] and Yashtimadhu kalka ^[15] were prepared according to standard protocol.

Cow ghee 1200 gm. was heated on low flame. Heating was discontinued as fumes aroused.

Freshly prepared Amalaki swaras 19,200 ml and Yashtimadhu kalka 150 gm. were added in the ghee.

Mixture was heated on a constant low flame on gas stove.

Mixture was stirred in between to avoid sticking of kalka to the bottom of the vessel.

On 1st day heating was done for 11 hours and on second day it took total 10 hours for process completion.^[16]

Thus, total 21 hours of heating was required to achieve the testing criteria.^[17]

It was filtered through a clean cotton cloth in its warm stage and was kept in a glass jar. Final quantity obtained was 600 gm.

· Physico chemical Analysis and Preliminary phytochemical screening:

AG was analyzed using various standard physico-chemical parameters such as acid value, saponification value, iodine value, peroxide value, specific gravity etc.(See table no. 2) Similarly it was screened for the various secondary metabolites like steroids, alkaloids, phenols, flavonoids, tannins and glycosides using standard methods.

Antiepileptic Activity:

Dose calculation:

The recommended therapeutic dose of medicated ghee is 40gm. in human being.^[18] The test drug was administered in animals by using extrapolation factor for mice (0.0026). ^[19]The study was carried out in three dose levels as AG X/2 = 0.05 gm/20gm (lower dose), X = 0.1 gm/20gm (medium dose) and 2X = 0.2gm/20gm (higher dose) for mice. For control group cow ghee was used. Standard drug was used in one group for comparison. Drugs were administered to animals considering their weight.

Maximal Electroshock Seizure (MES) model^[^20]

Animals were divided into five groups each comprising of eight animals as shown below.

Group I: Control (Cow ghee 5gm/kg orally and treated with Electro-convulsive shock 33mA, 0.2sec., using ear electrode).

Group II: Standard (Phenytoin 25mg/kg orally and treated with Electro-convulsive shock 33mA, 0.2sec., using ear electrode).

Group III: AG (2.5gm/kg orally and treated with Electro-convulsive shock 33mA, 0.2sec., using ear electrode).

Group IV: AG (5gm/kg orally and treated with Electro-convulsive shock 33mA, 0.2sec., using ear electrode).

Group V: AG (10gm/kg orally and treated with Electro-convulsive shock 33mA, 0.2sec., using ear electrode)

A pre-test was done using the above mentioned strength and animals showing occurrence of Tonic Hind Limb Extension (THLE) were selected for the study.

The first observation was taken after 24 hours of dosing for control and test drug groups i.e. on 2^nd day. For standard (Phenytoin) group dosing was done just 1 hour prior to observations.

2^nd day dosing was done after 60 minutes of first observations in case of control and test drug groups. Dosing was continued for next 5 days for all animals in each group.

The last observation was taken after 1hour of dosing of each animal from all groups on 7^th day.

Duration of Tonic Hind Limb Extension (THLE) was considered as the assessment parameter.

Pentylenetetrazole (PTZ) model^[^21]

Animals were divided into five groups each comprising of eight animals as shown below.

Group I: Control (Cow ghee 5gm/kg orally and treated with Pentylenetetrazole 60mg/kg i.p)

Group II: Standard (Sodium Valproate 312mg/kg orally and treated with Pentylenetetrazole 60mg/kg i.p)

Group III: AG (2.5gm/kg orally and treated with Pentylenetetrazole 60mg/kg i.p)

Group IV: AG (5gm/kg orally and treated with Pentylenetetrazole 60mg/kg i.p)

Group V: AG (10gm/kg orally and treated with Pentylenetetrazole 60mg/kg i.p)

Drug doses were administered orally to control and three test drug group animals. After 24 hours, PTZ was injected i.p to all the animals. One hour prior to PTZ induction, dosing for standard drug group was done. Each animal was kept in a separate plastic cage and was observed for presence or absence and onset time of clonic convulsions for a period of 60 minutes post PTZ induction. Percent protection offered by drugs was calculated.

Statistical analysis:

Data was presented as Mean ± SEM. 'Graph Pad Prism-5' was used to analyze the data. The test used was one way analysis of variance (ANOVA) followed by post-Hoc Dunnett’s test and the significance was set at p<0.05.

3. RESULTS:

Prepared AG was dark greenish in colour with Snigdha sparsha (Unctuous) and Amla Kashaya (Sour and astringent) in taste. Results observed through physicochemical analysis can be found in Table 2.

Table No. 2: Physicochemical parameters of AG

Parameter		Reading
Free Fatty acid	1.18%
Moisture	0.14%
Burto refractometer reading	43.00
pH	5
Specific Gravity	0.898
Wt/ml	0.82
Saponification value	277.695
Acid value	1.0854
Iodine value	53.8
Peroxide value	0.0397

Preliminary phytochemical screening of hexane extract of AG showed presence of alkaloids, flavonoides, tannins and phenols. (Table 3)

Table No. 3: Qualitative organic analytical data of AG (Hexane extract)

Analytical Parameter	Present/Absent
Alkaloids		Present
Steroids		Absent
Phenols		Present
Tannins		Present
Glycosides		Absent
Resins		Absent
Saponins		Absent
Flavonoids		Present

Effect of AG against Maximal Electro Shock (MES) seizures

Maximal electroshock produced hind limb extension seizures in all the experimental animals used. The anticonvulsant potential of AG against MES screening model is shown in Table 4. Pre treatment with a single dose of AG at all three dose levels showed reduction in the duration of THLE on second day when compared to control but it was not statistically significant. Seven days pre treatment showed dose dependant results. AG at dose 2.5 gm/kg reduced the duration of tonic hind limb extensions (P<0.01) when compared to the control. AG at doses 5gm/kg and 10gm/kg significantly reduced the duration of the tonic hind limb extensions (P<0.001) when compared to the control.

The standard antiepileptic drug, phenytoin showed significant protection against Maximal electroshock seizures in all the animals as expected.

Table no.4: Effect of AG against Maximal Electro Shock (MES) seizures

Group	After 24 hours of Drug treatment (Mean ± SEM)	After 7 days of Drug treatment (Mean ± SEM)
Group	THLE Duration (Seconds)
Control (Cow ghee) (0.1 gm/20gm)	16.5 ±1.439	19.38 ±1.475
Standard (Phenytoin (0.6mg /20gm)	1.25 ±0.6748 ***	0.625 ±0.4199 ***
AG X/2 (0.05 gm/20gm )	14.5 ±1.336	12.88 ±1.42 **
AG X (0.1 gm/20gm)	13.38 ±1.253	10.5 ±1.118 ***
AG 2X (0.2 gm/20gm)	13 ±0.8018	9.125 ±0.6391 ***

Values are expressed as mean± SEM (n=8) (compared to Control group) by using One way Analysis of Variance (ANOVA) followed by Dunnett's Multiple Comparison Test ** p< 0.01, *** p < 0.001

Effect of AG against PTZ‑ induced convulsions:

The standard drug sodium Valproate provided 100% protection. AG at the dose of (2.5 gm/kg) did not delay the onset of convulsions to any significant extent when compared with the effect produced by control. AG at dose levels (5gm/kg and 10gm/kg) showed significant delay in onset of clonic convulsions (p< 0.05 and p< 0.01) when compared with control. AG at dose (2.5, 5 and 10mg/kg) offered protection as (0% 12.5% and 25%) respectively. (Table 5)

Table No. 5: Effect of AG against PTZ induced convulsions

Group	Percentage of protection against seizure	24 hours (After drug treatment)
Group	Percentage of protection against seizure	Onset of clonic convulsions (seconds )
Control (Cow ghee) (0.1 gm/20gm)	0 %	5 ±0.5
Standard(Sodium Valproate) (6.24mg/20gm)	100%	Nil
AG X/2 (0.05 gm/20gm )	0%	9.875 ±2.386
AG X (0.1 gm/20gm )	12.5 %	8.375 ±1.1648*
AG 2X (0.2 gm/20gm )	25 %	11.63 ±2.146**

Values are expressed as mean ±SEM (n=8) (compared to Control group) by using One way Analysis of Variance (ANOVA) followed by Dunnett's Multiple Comparison Test * p < 0.05, ** p < 0.01

4. DISCUSSION:

The present study was aimed at evaluating the antiepileptic activity of Amalakyadi Ghrita using animal models. AG is a sidhha Ghrita preparation containing Amalaki and Yashtimadhu processed in cow ghee prepared by desi method, all possessing medhya activity.

According to Sharangdhar Samhita ^[18], general recommended proportion of kalka dravya to oil/ghee to drava dravya in the preparation of any Sneha paka is 1:4:16 however in AG, the specified proportion for the same is 1:8:128.^[8] It is noteworthy that in this formulation, the proportion of drava dravya is 16 times that of Sneha dravya which is substantially higher than routinely recommended proportion. The reason behind use of such a high proportion could be attributed to the fact that maximum extraction of active constituents in ghrita is expected to get the desired action of AG.

Cow ghee is known for its smritivardhaka (memory enhancing), buddhivardhaka (intellect promoting) and apasmarnashak attributes.^[13]Similarly the unique ability of cow ghee to imbibe and enhance attributes of the drug used in processing without losing its own properties is known “Sanskarasyanuvartanam’’.^[^22] So to rule out the exact action of unprocessed cow ghee and processed AG, cow ghee has been used as a control drug. Results also indicate that plain cow ghee showed positive results but AG definitely showed statistically significant positive results. These results are supportive of Sanskarasyanuvartanam property of Ghrita.

A pilot study was conducted to decide intensity of current required to develop THLE in this specific strain of mice. Mortality was observed at 50 mA and 40 mA current, all the animals showed presence of THLE at 33mA current without mortality, so this intensity was used for the study.

Maximal electroshock test is the most widely used animal model in antiepileptic drug discovery because seizure induction is simple and the predictive value for detecting clinically effective antiepileptic drug is high. This method identifies the drug with activity against generalized tonic-clonic seizures and partial seizures using clinically established antiepileptic drug.^[23]

PTZ test represents a valid model for human generalized myoclonic and absence seizures. PTZ induced seizure is most frequently employed in the preliminary screening of potential anticonvulsant drugs.^[24] The mechanism by which PTZ is believed to exert its action is by acting as an antagonist at the GABA receptor complex. ^[25]GABA is the major inhibitory neurotransmitter which is implicated in epilepsy. The enhancement and inhibition of the neurotransmission of GABA will attenuate and enhance seizure respectively.^[26]

Phenytoin Sodium is a commonly used effective antiepileptic drug in treatment of tonic clonic seizure i.e. Grand Mal Epilepsy. Sodium Valproate is the well established drug for treatment of Absence Seizure i. e. Petit Mal Epilepsy.^[27]Thus two drugs were used as the standard drugs in MES and PTZ induced seizure models respectively.

In MES test, treatment with AG at higher dose level after 7 days significantly reduced THLE in mice (P < 0.001). MES test serves to identify compounds which prevent seizure spread, corresponding to generalized tonic-clonic seizures in humans.^[28,29] Since, AG significantly inhibited THLE stage of generalized tonic-clonic seizures in MES test; it suggests the presence of anticonvulsant action.

In PTZ model, AG at (5mg/kg and 10mg/kg) dose levels showed protective effect against seizure induced by PTZ by delaying the onset of convulsions (P < 0.05 and P<0.01).Valporate increases turnover of gamma- amino butyric acid (GABA) and thereby potentiates GABAergic functions in some specific brain regions thought to be involved in the control of seizure generation and propagation. Hence it is quite possible that AG may additionally exert its anticonvulsant effect by increasing the levels of GABA in the brain.^[30]

Amalaki (E. officinalis) which is a major ingredient of AG possesses neuroprotective, free radical scavenging, antioxidant, anti‑inflammatory, antipyretic, analgesic, adaptogenic, antihypercholesterolemic and nephroprotective properties. As demonstrated in numerous preclinical studies. E. officinalis is also reported to possess radiomodulatory, chemomodulatory, chemopreventive, antimutagenic and immunomodulatory activities.^[31]It is a proven fact that the roots and rhizomes of Yashtimadhu (Glycyrrhiza glabra) are an efficient brain tonic. This drug is known to enhance blood supply in the CNS system and balances the sugar levels in the blood.^[32] Ethanolic extract of roots and rhizomes of Glycyrrhiza glabra Linn (10, 30, 100 and 500 mg/kg, i.p.) significantly and dose dependently delayed the onset of clonic convulsions induced by pentylenetetrazol. The dose of 100 mg/kg afforded protection to all animals.^[33] Glycyrrhiza glabra is reported to possess antioxidant, anti-inflammatory, antispasmodic, anti hyper glycemic properties.^[34]All the above data indicates multidimensional potential of both the ingredients which could be responsible for antiepileptic property of AG.

A formulation with similar ingredients but titled differently “panchagavya formulation” has been studied for it’s effect on pentelenetetrazol-induced seizures and maximal electroshock- induced seizures. Results indicate that formulation protected mice against tonic convulsions induced by maximal electroshock (500, 750mg/kg. po). This formulation slightly prolonged the seizure activity but did not protect mice against lethality induced by penteletetrazole. Furthermore it did not show neurotoxicity and is sedative in nature.^[35]

This formulation has the same ingredients but their ratio mentioned is different as E. officinalis Gaerth (10gm) Glycyrrhiza glabra Linn (10 gm) and cow ghee (80gm). Secondly form of the ingredients used is not specified. Study has been conducted using different dose levels than in our study. The above mentioned formulation was obtained as a gift sample from Go-vigyan anusandhan Kendra, Nagpur, India. Thus above study is different in all the mentioned aspects than our study.

Significant antiepileptic activity of AG could also be attributed to presence of various phyto constituents like flavonoids, tannins. In the CNS, several flavones bind to the benzodiazepine site on the GABA_A receptor resulting in sedation, anxiolytic or anti-convulsive effects. The in vivo studies show that flavonoids are able to be absorbed after oral administration, pass the blood-brain barrier and do have various effects on the CNS.^[36]

From our study we can conclude that multidimensional therapeutic potential of both the ingredients and presence of different phyto constituents in the formulation may singularly or in combination be responsible for antiepileptic activity of AG.

5. CONCLUSION:

AG has shown significant antiepileptic activity in MES (p<0.001) and PTZ (p<0.05) models.

6. ACKNOWLEDGEMENT:

Authors are thankful to the HOD and Professor Dr. Vijaya Pandit and her colleagues for providing CPCSEA approved animal house facility. Authors are thankful to Dr. Vasudevan Mani, Associate Professor, Brain Research Laboratory, Malaysia for sharing his research articles related to the subject.

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Received on 01.10.2015 Modified on 16.10.2015

Res. J. Pharmacology & P’dynamics. 7(4): Oct.-Dec., 2015; Page 155-160

DOI: 10.5958/2321-5836.2015.00030.0