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Journal of Herbal Medicine and Toxicology 1(1) 9-14 (2007) ISSN: 0973-4643

Review Article

HERBAL ANTICONVULSANTS

VYAWAHARE, N.S.1 , KHANDELWAL, A.R.2, BATRA, V.R.2 AND NIKAM, A.P.3

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AISSMS College of Pharmacy, Kennedy Road, Pune. 2Louisiana State University Health Sciences Center Shreveport Louisiana. U.S.A. 3BVP's Poona College of Pharmacy, Erandawane, Pune 411038. E-mail:[email protected] Abstract: Epilepsy has now become the most serious brain disorder, which accounts for about 1% of the world's burden of diseases. A number of synthetic antiepileptic drugs are available in practice, however their effectiveness does not hold true with the entire range of population suffering from this disorder. Moreover the side effects and the drug interactions are major restrictions in its clinical utility. On the other hand, herbal medicines are widely used across the globe due to their wide applicability and therapeutic efficacy coupled with least side effects, which in turn has accelerated the scientific research regarding the antiepileptic activity. In this overview we have summarized the current herbal antiepileptics and their research advancements. Key words: Convulsions, Herbal anticonvulsants, Picrotoxin, Tonic-clonic.

INTRODUCTION

Epilepsy is characterized by recurrence of seizures, defined as the manifestation of paroxysmal and disordered neuronal discharges in the brain. Seizures can vary widely in their clinical presentation, depending on site, extent and mode of propagation of the paroxysmal discharge and hence now looked at as spectrum of clinically different varieties rather than a single disease [1,2]. Epilepsy is becoming the most serious brain disorder and affects about 40 million people and about 100 million will be affected at some time in their life. Overall it accounts for 1% of the world's burden of diseases, and the prevalence rate is reported at 2%. In addition, the incidence rate for primary generalized tonic ­ clonic and absence seizures is highest in infants and children [2,3]. A large number of agents called antiepileptic drugs are available to treat various types of seizures with the objective to reduce seizure frequency and severity within a framework of an acceptable level of side effects. The ideal anti-seizure drug would suppress all seizures without causing any unwanted effect. Unfortunately the drugs used currently not only fail to control seizure activity in some patients, but they frequently cause side effects (Table 1). In addition safety, tolerability, efficiency, expenses especially in 9

long term therapy, serum drug monitoring etc. are other limitations with synthetic antiepileptic drugs [1,2]. Further, a large number of drug interactions seen with almost all current antiepileptic drugs make it more difficult to attain easy control on seizures. [4]. On the other hand, the world health organization has estimated that perhaps 80% of the world's population relies chiefly on traditional medicine for primary health care needs. Moreover, allopathic science may gain much from the study of such systems and important allopathic drugs like digitalis, quinine, atropine and several others have originated from plant sources [5]. The discipline of Ayurveda (An alternative system of medicine) has existed in India from millennia with the objective to treat poor health with economical medicines obtained from herbs [6]. Likewise, different regions across the globe inherit their traditional system of medicine wherein, in today's globalized era these traditional systems should not be restricted to their native origins but rather be made accessible and used throughout the human populace. With this regards herbal anticonvulsants that are successfully exploited are reviewed as under. Herbal anticonvulsants: Hexanic fraction of Rubus brasiliensis (300mg / kg) prevented the

J Herb Med Toxicol pentylenetetrazole (70mg/kg/ip) induced seizures. The fraction was found to contain a benzodiazepine like principle and hence indicated possible involvement of GABA­A receptors. This involvement is further supported by reversal of anxiolysis in rodents induced by lumozenil, a specific GABA ­A ­ benzodiazepine receptor antagonist [7]. The ethanolic extract of leaves of Albizzia lebbeck have been shown to protect the mice from maximum electroshock, electrical kindling and pentylenetetrazole-induced convulsions. The bioassay-guided fractionation further indicated that the activity lies in the methanolic fraction of chloroform soluble part of ethanolic extract of leaves [8]. Lavandula stoechas L has been used for a long time in traditional medicine as an anticonvulsant. Gilani et al validated its anticonvulsant effect. The study revealed that aqueous methanolic extract of L. stoechas flowers (600mg/kg) significantly reduced the severity and increased the latency of onset of convulsions induced by pentylenetetrazole. Moreover, in isolated rabbit jejunum preparations, it caused a dose dependent (0.1­1.0mg/ml) relaxation of spontaneous contraction and inhibited K+ induced contractions thereby, suggesting calcium channel blockade. Further, pretreatment of the jejunum preparation with L. Stoechas produced a dose dependent shift of the Ca++ dose response curve to the right similar to the effect of standard calcium channel blocking activity [9]. A study with water extract of Scutellariae radix reported its anticonvulsant activity against maximal electroshock induced seizures and ED50 was found to be 3.6 g/kg. On the other hand, it did not show any significant protection against Pentylenetetrazole induced seizures. This study further demonstrated that, extract had no significant effect on GABA stimulated chloride uptake leaving mechanism to be revealed [10]. Pimpinella anisum is a folk remedy in the Iranian traditional medicine. The essential oil of fruits of the plant was found to be anticonvulsant as it suppressed the tonic convulsions in mice induced by pentylenetetrazole and maximum electroshock treatment. In addition, elevation in the threshold of PTZ induced clonic convulsions is also reported [11]. Malaya Gupta et al found that pretreatment with methanolic extract of roots of Moringa oleifera caused significant protection against strychnine and PTZ induced convulsions. The overall CNS 10 depression along with potentiation of hypnotic activity of pentobarbitone sodium as well as diazepam is also recorded. The exact mechanism of its anticonvulsant activity is not revealed but attributed to generalized CNS depression [12]. Hypericum perforatum L is mentioned in Iranian traditional medicine for its anticonvulsant activity. Hosseinzadeh et al studied activity of its aqueous and ethanol extract of aerial part in mice to scientifically evaluate the use of this plant. These extracts were tested (0.1-1 gm/kg i.p) against pentylenetetrazole and MES induced convulsions. In PTZ, the extract delayed the onset of tonic convulsion and protected the mice against mortality while in MES model the result was not significant. Furthermore, the study also reported that, a nitric oxide synthase inhibitor (L NAME) (1-10mg/kg i.p), reduced anticonvulsant effect of the extract, indicating possible role of nitric oxide pathways [13]. Thymoquinone is major constituent of Nigella sativa seeds, a traditional medicine claimed to be useful in convulsions. A study conducted for anticonvulsant effect of Thymoquinone using pentylenetetrazole and maximum electroshock induced seizures found that a dose of 40 mg/kg and 80 mg/kg prolong the onset of seizures and reduce the duration of myoclonic seizures induced by PTZ treatment but not by MES. The complete protective effect against mortality was reported in both the tests. In addition, flumazenil (10mg/kg), an antagonist of benzodiazepine (GABA A­BZD receptor complex) inhibited the prolongation of seizure latency without affecting the duration of myoclonic seizures while pretreatment with different doses of naloxone (0.1-3 mg/kg i.p) inhibited the prolongation of myoclonic seizures as well as reduced the duration of myoclonic seizures induced by thymoquinone. These results clearly suggest the effect of Thymoquinone in PTZ model probably through an opoid receptor mediated increase in GABAnergic tone [14]. The essential oil of leaf of laurus nobilis linn has been used as an antiepileptic remedy in Iranian traditional medicine. The scientific evaluation showed protection of mice against tonic convulsions induced by MES and PTZ treatment. The protection was more significant against PTZ induced convulsions compared to MES [15]. Aqueous extract of Leonotis leonurus L was tested for its anticonvulsant action against Pentlenetetrazole (90mg/kg), picrotoxin (08mg/kg), N- methyl- DL-

Vyawahare et al.

Table 1: Major side effects of commonly used anticonvulsants [32].

DRUG Phenobarbital Phenytoin Trimethadone Ethosuximide Carbamazepine Primidone Sodium valproate Lamotrigine SIDE EFFECTS Dizziness, lethargy, hypotension, aponea, megaloblastic anemia, Liver damage and so on. Nausea, skin rashes blood dyscarasias, hyperglycemia cardiac arrhythmias and so on. Drowsiness, G.I.distress, vertigo, diplopia, epistaxis, alopecia, nephrosis, foetal malformation and so on G.I. distress, euphoria, confusion, myopia, urticaria, vaginal bleeding and so on. Dizziness, ataxia, drowsiness, hallucinations, dermatologic sweating, genitourinary albuminaria, hypotension, liver dysfunction and so on. Lethargy, ataxia, vertigo, irritability, severe skin rashes, lymphadenopathy, impotence, visual disturbances, lupus like reactions and so on. Nausea, vomiting, indigestion, sedation, abdominal cramps, fetal hepatic failure, alopecia, irregular menses, acute pancreases, blood dyscarasias and so on. Dizziness, ataxia, blurred vision, vomiting, skin rashes, Stevens Johnson syndrome, disseminated intravascular coagulation.

Table 2: Common drug-drug interactions [4].

Antiepileptic drug Other drugs Caffeine Cimitidine /Ranitidine Codeine Felbamate Miconazole Rifampicin Sodium valproate Interactions Reduces or abolishes the hypnotic effect of pentobarbitone Pentobarbitone reduces the absorption of cimitidine while cimitide increases metabolism of pentobarbitone Increases serum level of pentobarbitone. Increases serum level of pentobarbitone. Reduce in the activity of rifampicin by increase in the clearance. Increase in phenobarbitone level leading to excessive sedation. Decrease in serum phenobarbitone level. Allopurinol Increase in serum levels of carbamazepine. Cholestyaramine/ Reduction in absorption of carbamazepine. Colestipol Transient increase in serum carbamazepine. Leads to hyponatraemia. Cemitidine / Ranitidine Marked increase in serum carbamazepine levels leading to toxicity. Diuretics Marked increase in serum carbamazepine levels leading to toxicity. Isoniazid Carbamazepine levels are reduced leading to its poor seizure control. Metronidazole Primidone Antacids Reduced serum phenytoin levels and thus loss of seizure control. Chlorpheniramine Phenytoin intoxication.

Barbiturates

Carbamazepine

Phenytoin

Table 3: Marketed Herbal Preparations Claiming anticonvulsant use [31].

Brand name APSA Ned forte Zandopa Raswatarishta Mfg Company IMIS Charak Zandu Baidyanath Ingredients Withania somnifera, Hemamakshika Blasma, Rajatha Blasma, Extract of Rasona Vacha, Atimadhura, Mandukaparni, Kushta, Jatamansi, Parasika Yavani, Brahmi, Shatavari, Kushmanda, Sarpagandha, Triphal, Jeeraka, Krishana Beeja,Shirisha Beeja,Guduchi And Apapajitha. Akika Bhasma, Mass Extracts Of Yashthimadhu, Brahmi, and Vacha. Mucuna Pruriens. Brahmi, Shatavar, Vidara, Haritaki, Ushri, Sontha, Saunf, Nishoth, Laung Papal, Vacha, Kust, Ela, Ashvagandha Bahera Giloe, Vidanga, Dachini, Dhataki, Jaggery (Gud). Ras Sindoor, Kasturi, Swarna Blasma, Manashila and Hartal, Ghrit Kumari

Chaturbhuj Ras (Swarna Ambar Baidyanath Yukta) Chaturmukha Ras. Baidyanath (with gold)

Parad, Gandhak, Lauha, Bhasma, Abhrak, Bhasma,Swarna Bhasma

aspartic acid (400 mg/kg) and bicuculline (20mg/kg) induced seizures. The different doses of (200,400 mg/ kg) extract showed significant delay in onset of tonicclonic convulsions in all except bicuculline model. The result suggested that, the extract may probably act by non-specific mechanism since it affects both GABAnergic and glutamenergic system [16]. Dried roots of delphinium denudatum are a popular folk remedy for the treatment of epilepsy in traditional Unani system of medicine. A study of anticonvulsant screening of ethanolic extract and aqueous fraction of the plant against MES, PTZ, bicuculline, picrotoxin and strychnine induced convulsions was carried out wherein. Ethanolic extract showed dose dependent

anticonvulsant action on seizures induced by PTZ and bicuculline while aqueous extract showed activity against pentylenetetrazole and MES induced convulsions especially inhibition of hind limb extension [17]. The anticonvulsant effect of Mitragyna africanus stem bark against strychnine (2mg/kg) induced convulsions in rats have been reported causing protection by increasing the period of onset of convulsions along with decrease in the number of episodes of spasms [18]. Cyperus articulatus is used in the traditional medicine in Africa and Latin America for various disorders of CNS including

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J Herb Med Toxicol epilepsy. The methanolic extract of rhizomes was tested for its anticonvulsant action against pentylenetetrazole, MES, strychnine and picrotoxin induced convulsions. The extract was effective in all models except in picrotoxin. The ED50 for the PTZ and MES model was found to be 306mg/ kg and 1005 mg/ kg respectively. Further studies suggest that the aqueous extract of Cyperus articulatus showed dose dependent reduction in spontaneous epileptic form discharge and NMDA induced depolarization in rat cortical wedge preparation at concentration at which L-amino-3-hydroxy-5methyl-isoxazole-4propionic acid (AMPA) induced depolarization are not affected. This indicates that the extract may contain components acting as AMPA antagonist responsible for the possible antiepileptic action [19]. Ferula gummosa Boiss is a reputed drug in Iranian traditional medicine and has been used as antiepileptic remedy. The evaluation of seed acetone extract carried out by Muhammad Sayyah et al reported its anticonvulsant effect against pentylenetetrazole and MES induced convulsions. The ED50 was found to be 198.3mg/ kg in MES and 55mg/ kg in PTZ model respectively [20]. The various functions of petroleum ether extract of Butea Monosperma wer e studied for its anticonvulsant activity and active constituent was found to be triterpene in the n-hexane ethyl acetate (1:1) fraction. This triterpene significantly inhibited seizure induced by MES, pentylenetetrazole, electrical kindling and combination of lithium sulphate with pilocarpine nitrate while was not effective against strychnine and picrotoxin induced convulsions [21]. Mimosa pudica L is a common plant in moist waste ground, lawn, open plantation and weedy thickets and traditionally claimed to be useful in many diseases related to the nervous system. E Neo bum et al studied anticonvulsant action of various doses of decoction (400-500 mg/kg) of Mimosa pudica leaves against strychnine (25mg/kg) and PTZ (70 mg/kg) induced convulsions. The result of the decoction was compared against the control and clonazepam (0.1 mg/kg) treated mice, where survival of animals for more than 10 minutes was regarded as anticonvulsant effect. The percentage of the mice protected with the test drug was 12.5% (500 mg/kg) and 100 % (4000mg/kg) in case of strychnine model while the same doses showed 12.5 % and 80 % protection respectively in the PTZ model. In addition, the decoction did not show significant effect against 12 picrotoxin (7.5 mg/kg) induced seizures. This further suggested the possible use of the drug in generalized clonic seizures in man (PTZ model) through GABAnergic neurotransmission. The inhibition of strychnine induced seizures highlights its indication through glycine receptors. Overall the study revealed anticonvulsant effect of the drug through modulation of multiple neurotransmission [22]. Sonawane et al screened the spectrum of anticonvulsant activity of Myristica fragrans using various models. Animals were pretreated with various doses (10, 30,100 mg/kg) of the drug. In MES model, drug showed significant reduction in duration of hind limb extension with 10 mg/kg dose and effect was dramatically reduced with increase in dose. Similar dose dependent results were obtained in PTZ model by delaying myoclonic spasm. The delayed onset of clonic convulsions were recorded in picrotoxin model while in case of lithium pilocarpine induced status epilepticus, the gradual decrease in the progression as well as severity of status epilepticus was reported with increased dose. The study concluded with significant anticonvulsant activity of drug against various models of epilepsy but was unable to reveal the exact mechanism of its action [23]. In the traditional system of medicine, roots and rhizomes of Glychrrhiza glabra have been in use since centuries. Ambawade et al. [24] reported anticonvulsant action of its ethanolic extract of roots and rhizomes. The extract significantly and dose dependently delayed the onset of clonic convulsions induced by PTZ. Moreover, the dose of 100mg/kg offered protection to all animals. Benincasa hispida fruit, is used as a vegetable in India and other tropical countries. Anil Kumar et al. studied methanolic extract of Benincasa hispida using PTZ, strychnine and picrotoxin and MES model in mice at dose level ranging from 0.2 -1.0 gm/kg, i.p. The extract at 0.2-0.6 gm/kg significantly inhibited the hind limb extension induced by MES and at 0.40.6 gm/kg significantly increased the latency of convulsion and death induced by PTZ and Strychnine respectively [25]. In Ayurveda it is claimed that leaves of Ficus religiosa possesses anticonvulsant activity. The extract obtained from the leaves of Ficus Religiosa was evaluated for its anticonvulsant activity against pentylenetetrazole (60mg/kg, i.p) induced convulsion in albino rats. The study revealed 80 to 100 %

Vyawahare et al. protection against PTZ induced convulsions when given 30-60 minutes prior to induced convulsion respectively [26]. Nantenine, an amorphine alkaloid, found in several vegetal species is used in traditional medicine. A screening of anticonvulsant activity of different doses of nantenine using PTZ (100 mg/ kg) and MES models revealed its significant biphasic activity. It is found to be anticonvulsant at low doses (20-50 mg/ kg i.p) against both models while convulsant at higher doses (above 75 mg/ kg). The earlier reports of biphasic action of nantenine on Na + K + ATPase, suggested that convulsant effect appears to be related to inhibition of Na +K + ATPase at high doses while decrease in Ca ++ influx into the cell at low doses may be the reason for its anticonvulsant effect [27]. Stigma of Crocus sativus L is used in traditional medicine for its anticonvulsant property. Hossein et al carried out its scientific validation of various doses of aqueous extract (0.08,0.32,0.56,0.8 gm/kg) and ethanolic extract (0.2,0.8,1.4,2 gm/kg) in mice. The study reported that it delayed the onset of tonic convulsions in PTZ (90 mg/kg) model while reduced the duration of tonic seizures in MES (150mA, 50 Hz, 0.2sec) model, indicating partial protection against epilepsy. The exact mechanism of action is not clear, but attributed to its reported generalized CNS depressant effect [28]. Composite preparation: Most of the marketed preparations of alternative medicines consist of more than one drug in appropriate combinations (table 3). This could be one of the reasons for more promising results compared to the individual drug tested at laboratory level; hence standardization of marketed preparations can impart good scientific knowledge to develop more and more effective herbal anticonvulsants. Achliya et al.[29] studied brahmi Ghrita, one of the panchgavya formulation claimed as an anticonvulsant in Ayurveda containing Bacopa moneri (48g), Acorus calamus (4 g), Evolvus alsinoids (4g), Sausserea lappa and cow's ghee (80 gm). Anticonvulsant effect of various doses (100,300,500 and 750 mg/kg p.o) was tested against PTZ (80 mg/kg) and maximum electroshock induced seizures (45mA, 0.2 seconds) in mice. The study reported the significant delay in clonic seizure induced by PTZ and dose dependent decrease in duration of hind limb 13 extensor phase in MES model. This study predicted possible mechanism of the formulation mediated through chloride channel of the GABA or benzodiazepine receptor complex, however did not reveal any firm conclusion [29].

CONCLUSION

The present allopathic pharmacotherapy in the management of epilepsy is based upon the nature and type of epilepsy. It is reported that about 30 % of patients require polytherapy [30] for better control, which in turn increases the chances of drug-drug interaction and side effects (Table 4). The present review clearly revealed the anticonvulsant potential of various herbal medication that are now documented scientifically. The reports of possible mechanism of action have shown that the identification of particular fraction and or active constituent can further provide more extensive results. Comparatively lesser side effects and interactions associated with these herbal remedies can make the anticonvulsant treatment more rationale and patient friendly. The review also found that certain herbal drugs mentioned in various traditional systems of medicines across the globe have not been exploited up to the desired level, and these claims could be a better target for the development of more and more alternatives to allopathic anticonvulsants.

ACKNOWLEDGMENTS

The authors extend their sincere thanks to Dr. K.G. Bothara, Principal, AISSMS College of Pharmacy, Dr. S.L. Bodhankar, Poona College of Pharmacy, Pune for their guidance in the preparation of this manuscript. We are also thankful to our students Miss Esha Anand, Miss Sakshi Ahuja and Miss Priyanka Baramate for their timely help.

REFERENCES

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