Epilepsy is a major neurological disorder and up to 5% of the world population develops epilepsy in their lifetime. The current therapy of epilepsy with modern antiepileptic drugs is associated with side effects, dose-related and chronic toxicity, as well as teratogenic effects, and approximately 30% of the patients continue to have seizures with current antiepileptic drugs therapy (Devinsky, 1995; Holmes, 1993; Mattson, 1995; Smith and Bleck, 1991). Epilepsy can affect all ages (Hauser et al., 1991), it is probable that the prevalence is higher in less developed countries because of higher incidence of antecedent factors such as brain infections, cranial and perinatal traumas and parasitic infections. Although the prognosis for controlling of seizures in most patients in terms of seizure control, remission and withdrawal of medication (Cockerel et al., 1993; Richens and Perucca, 1993). Epilepsy is characterized by recurrent episodes of seizures. A seizure is due to abnormal discharge of some neurons in the brain. Antiepileptic drugs may have a stabilizing influence on neuronal membrane; prevent detonation of normal brain cells by the focal discharge, these drugs act only on those neurons which are firing repeatedly. Some drugs reduce low threshold Ca2+ current and abolish absence seizures whereas some drugs increase gama amino butyric acid (GABA) activity in the synapse causing neuronal inhibition hence antiseizure effect. Glutamic acid causes increased synaptic transmission. A variety of glutamic acid receptors is N-methyl-d-aspartate (NMDA) receptors and reduction of NMDA receptor activity reduces seizure development (Manna et al., 2005). All the currently-available antiepileptic drugs are synthetic. Medicinal plants used for the therapy of epilepsy in Traditional Medicine (TM) have been shown to possess promising anticonvulsant activities and can be invaluable sources of new antiepileptic drugs (Kabir et al., 2005; Pradhan et al., 2007; Sridharan, 2002; WHO, 2001). Many people in developing countries may not receive basic treatment due to high cost, unavailability and untoward effects associated with the available antiepileptic drugs. Therefore, many people in the developing countries still rely on TM for their basic health care needs. World health organization (WHO) encourages the addition of herbal medicines of proven safety and efficacy in the healthcare programs of developing countries (Amos et al., 2001). Scientific research is needed to provide evidences of the safety and efficacy of beneficial medicinal plants. Thus a need arises for new agents with greater efficacy, negligible or reduced side effects and devoid of unfavourable drug interactions unlike most antiepileptic drugs in the market today.
Epilepsy is a collective term used for a group of chronic seizure disorders having in common, sudden and transient episodes (seizures) of loss or disturbance of consciousness, usually but not always with a characteristic body movements (convulsions) and sometimes with autonomic hyperactivity. Epilepsy can be classified into two major groups.
This is characterized by sudden loss of consciousness, followed by generalized tonic, followed by clonic convulsive movements. This is followed by a period of headache, drowsiness, confusion and sleep. The attack may be accompanied by tongue biting, frothing at the mouth and in continence (French et al., 2004; Gerlach and Krajewski, 2010; Kwan and Sander, 2004).
It consists of sudden cessation of ongoing conscious activity without convulsive movement and without loss of postural control. The patient appears to go blank for one second to one minute, and may be associated with bilateral clonic motor activity such as eyelid blinking. The epileptic seizures were caused by “occasional, sudden, excessive, rapid local discharge of grey matter”. Modern electrophysiology has amply confirmed this. The characteristic patho physiologic event in a seizure is believed to be paraxysomal depolarization shift of neuronal membrane potential and associated burst discharge. Excitatory neurotransmitters, such as aspartate and glutamate are thought to be involved in the initiation and spread of seizure discharges and the inhibitory transmitter GABA is believed to be responsible for termination of seizure activity. The underlying neuro chemical defect in epilepsy may be a functional impairment in the inhibitory GABA mechanism.
For including convulsion commonly used techniques are:
1. Electrical stimulation of brain by maximal electro shock (MES) induced method in rats.2. Chemical stimulation: Chemical commonly used is pentylentetrazole (PTZ), picrotoxin (PIC), bicucullin (BIC), isoniazid (INH).
Approximately 75% of all cases of epilepsy have no known cause. This is referred to as idiopathic epilepsy. The other 25% of cases may be due to trauma to the foetus during pregnancy or during birth, poisoning (lead poisoning, environmental contaminants), viral or bacterial infection (meningitis), alcohol or other drug abuse, head trauma (car accident or blow to the head), alteration in blood sugar levels, brain tumour, or stroke. In most cases, epilepsy is not inherited. However, a person may inherit a predisposition or tendency to have epilepsy if they are subjected to specific conditions. People who do not know the cause of their epilepsy often feel more anxiety about having the disorder. However, when the cause of epilepsy is unknown, the prognosis for epilepsy is not necessarily any worse.
Seizures may have many different appearances, which can be difficult to recognize. Some of the following may be indications that a seizure is occurring. Look for and make note of particular patterns of behaviour if they occur too often to be puted to chance.
● Day dreaming or short attention blackouts● Sudden falls for no reason● Lack of response for short periods of time● Unusual sleepiness and/or irritability when awakened from sleep● Rhythmic movements of the head (head nodding) or head dropping● Rapid blinking or upward eye rolling● Frequent unwarranted complaints from the child that things look, sound, taste, smell or Feel “funny” or different than they actually are● Sudden bowing or bending movements by babies who are sitting down● Sudden stomach pain followed by sleepiness or confusion● Repeated movements or jerking movements that look out of place or unnatural● Memory gaps● A blank stare followed by repetitive, meaningless movements● Dazed behaviour with the inability to communicate or talk for a brief period of time● Bed wetting or waking with a bitten tongue for no apparent reason● Lip smacking, chewing or swallowing
Approximately 1 to 2% of all people have epilepsy. 70 to 80% of those with epilepsy develop it before the age of 18 years. Of these, 44% develop epilepsy before age 5. There is a 10% lifetime risk of having at least 1 seizure. Depending on the type of seizure, 20 to 95% of individuals will go on to have more than 1 seizure, at which time they may be diagnosed as having epilepsy. Seizures are seen very frequently in the first 10 years of life. This may be due in part to the low seizure threshold of some children. As the child's brain matures, the seizure threshold rises, making the child more resistant to seizures. As a result, most people who develop seizures during childhood or adolescence tend to experience a reduction in the intensity and frequency of seizures as they approach adulthood.
Anticonvulsant drugs are used to control the convulsions by inhibiting the discharge and then producing hypnosis. Although several anticonvulsant drugs are available to treat convulsion, the treatment of epilepsy is still far from adequate because of their side effects and drug interactions. Thus there is a need for new more effective anticonvulsant drugs for intractable convulsion. In recent years research on medicinal plants has attracted a lot of attention worldwide. However nature is a rich source of biological and chemical diversity and a number of plants have been used in TM remedies and some are used in epilepsy also. Herbal medicines are widely used globally due to their wide applicability and therapeutic efficacy with low adverse effects. Several medicinal plants have been studied for their anticonvulsant activity. The researchs have been done at molecular level and several significant phyto-chemicals have been isolated. The present review is aimed at collecting data on promising medicinal plants that have anticonvulsant activity. The article refers to several plants with anticonvulsant properties.
The most popular and widely-used animal seizure models are the traditional MES and PTZ tests. The MES test is the most frequently-used as an animal model for identification of anticonvulsant activity of drugs for the generalized (grand mal) tonic-clonic seizures (Oliveira et al., 2001). This model is based on observation of the stimulation by repeated electrical pulses induce in different neuronal structures one characteristic standard of epileptic activity (Quintans-Júnior et al., 2002). PTZ-induced seizures test is considered as an experimental model for the generalized absence seizures and also a valid model for human generalized myoclonic seizures and generalized seizures of the petitmal type. The MES test serves to identify compounds which prevent seizure spread, corresponding to generalized tonic-clonic seizures in humans. Currently-used anticonvulsant drugs (phenytoin, carbama zepines) effective in therapy of generalized tonic-clonic and partial seizures have been found to show strong anticonvulsant action in MES test. Similarly, we found that treatment with PTZ-induced seizure in rats significantly reduce the duration of convulsion and delayed the onset of clonic convulsion. PTZ may cause seizures by inhibiting Cl+ channels associated with GABA receptors (Bum et al., 2001). Since PTZ has been shown to interact with the GABA neurotransmition and PTZ-induced seizures can be prevented by drugs that enhance GABA A-receptor-mediated inhibitory neurotran smission such as BDZs and phenobarbital, the antagonism of PTZ-induced seizures suggests the interaction with the GABA-ergic neurotransmission. The effect of the EEGS in the PTZ test could therefore suggest antiepileptic efficacy against the abovementioned seizures type in man. The MES and PTZ models are widely believed to be predictive of activity in common form of human epilepsy. All currently available AEDs those are clinically effective in the management of generalized tonic-clonic and partial seizures such as phenytoin, carbamazepine and lamotrigine (Rho and Sankar, 1999). They act by modulating neuronal voltage gated Na+ channels (Wickenden, 2002). The bioactive constituents which possess anticonvulsant acivity that may be beneficial in the management of grand mal epilepsy and lend credence to the use of the plant in the management of epilepsy in TM. Several biochemical hypothesis have been advanced involving the inhibitory GABA-ergic system and the system of the excitatory amino acid glutamate and aspartate.The mechanism by which PTZ is believed to exert its action is by acting as an antagonist at the GABA A receptor complex. Drugs protecting against tonicclonic seizures induced by PTZ are considered to be useful to control myoclonic and absence seizures in humans. The antiepileptic drugs are act by delayed tonic convulsion and mortality. The BDZ site in the GABA A receptor and T-type Ca2+ currents could be targets for the mechanisms of action of extract. These studies demonstrated unequivocally that like Phenytoin and possessed anticonvulsant activity. In the MES test since, inhibition of the MES test predicts the activity against generalized tonic clonic and cortical focal seizures. Hence it is suggests that the methanolic extract of the stem barks of the plant is useful in suppressing generalized tonic clonic seizures. Several drugs are thought to inhibit the seizures by regulating GABA mediated synaptic inhibition through an action at distinct sites of the synapse. Researchers are gaining new insight in to the TM in assisting the body to maintain its own self healing systems while preventing debilitating effects of chronic diseases, like epilepsy (Ambawade et al., 2002; Sudha et al., 2002).
A large number of drugs are available to treat various types of seizures to reduce seizure frequency and severity with an acceptable level of side effects. The ideal anti-seizure drug would suppress all seizures without causing any sideeffect. Unfortunately drugs used currently not only fail to control seizure in some patients, but they cause side effects. In addition safety, acceptability, competence, expenses in long term treatment, serum drug monitoring and drug interaction (Sirtori, 2000). A large number of drug interactions seen with almost all current antiepileptic drugs make it more difficult to attain easy control on seizures. An alternative system of medicine has existed in India from millennia with the objective to treat poor health with economical medicines obtained from herbs. Likewise, different regions across the globe inherit their traditional system of medicines 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 population. With this regard herbal anticonvulsants that are successfully exploited (Bodhankar2005 and Vyawahare, 2005; Nayak, 2004; Barar, 2004; Vyawahare et al., 2007). GABA is the major inhibitory neurotransmitter in the brain while glutamic acid is an excitatory neurotransmitter in the brain. The inhibition of GABA neurotransmitter and the enhancement of the action of glutamic acid have been shown to be the underlying factors in epilepsy. Drugs act against seizures induced by MES, PTZ, PIC and NMDLA and also delayed the latency of the seizures. Antiepileptic drugs that block MESinduced tonic extension are known to act by blocking seizure spread. Moreover, drugs that inhibit voltage-dependent Na+ channels, such as phenytoin can prevent MES-induced tonic extension. However, phenobarbitone is as effective against electrically-induced convulsion as it is against PTZ induced convulsions and phenobarbitone is known to reduce the electrical activity of neurons within a chemically-induced epileptic focus in the cortex, while diazepam does not suppress the focal activity but prevents it from spreading. Diazepam had anticonvulsant effect on both PTZ-induced seizures and MESinduced seizures. This is consistent with the report that BDZ agonists such as diazepam, clonazepam, are more potent in the prevention of PTZ-induced seizures than in that of MESinduced tonic seizures. PTZ may elicit seizures by inhibiting GABA-ergic mechanisms. Antiepileptic drugs, diazepam and phenobarbitone, are believed to produce their effects by enhancing GABA mediated inhibition in the brain. It is, therefore, possible that the anticonvulsant effects shown in this study by the drugs against seizures produced by PTZ might be due to the activation of GABA neurotransmission. Since the extract similarly antagonized seizures elicited by PTZ in mice, it is probable, therefore, that it may also be exerting its anticonvulsant effects by affecting GABA-ergic mechanisms. PIC also produced seizures in all the mice used. PIC is known to elicit seizures, by antagonizing the effect of GABA via blocking of the chloride channels linked to GABA A-receptor. The diazepam and phenobarbitone were shown to antagonize the effect of PIC while the extract was also shown to delay the latency of PIC–induced seizures, suggesting that the extract may be affecting GABA-ergic mechanisms, probably by opening the chloride channels associated with GABA receptors. BIC is a selective antagonist of GABA at the GABA Areceptors20. The fact that the extract did not affect the seizures induced by BIC, suggests that its effect on GABA-ergic mechanisms may not be via the stimulation of GABA Areceptors. NMDLA was also shown to elicit seizures in all the mice used. NMDLA, a specific agonist at the NMDA receptors, mimics the action of glutamic acid and thus induces seizures by enhancing the glutaminergic system. It is not surprising that the standard drugs, diazepam and phenobarbitone, did not alter NMDLA-induced seizures to any significant extent. In this study, the extract was shown to delay the latency of seizures induced by NMDLA. It may, therefore, be exerting its anticonvulsant effect partly by affecting glutaminergic mechanisms. Based on the present state of knowledge of the chemical constituents of the extract, it is not possible to pute with certainty its anticonvulsant effect to one or several active principles among those detected in the screening. However, triterpenic steroids and triterpenoidal saponins are reported to possess anticonvulsant activity in some experimental seizure models such as MES and PTZ. Some alkaloids, monoterpenes, flavonoids also have protective effects against PTZ, PIC, and NMDLA-induced convulsions. It is worthwhile to isolate the bioactive principles, which are responsible for these activities; the process has commenced in our laboratory. These findings justify the traditional use of this plant in the control and/or treatment of convulsions and epilepsy (Bialer et al., 2004; Bialer, 2006; Birbeck et al., 2007; Chisholm, 2005; Dwivedi, 2001; Dwivedi and Smar, 1994; Fisher et al., 2005; French et al., 1999; Huguenard, 1999; Kwan and Brodie, 2000; Mohanraj and Brodie, 2003; Rogawski and Loscher, 2004; Wagh et al., 2011).
A significant reduction in the time required for the recovery (righting reflex) was observed in this study, which proves that PHE was providing a beneficial effect in controlling MES induced seizures. The administration of PHE significantly increased the brain levels of serotonin, dopamine and noradrenaline, which could be puted to the significant protection offered against MES induced seizures. The increase in the brain monoamine level by inhibiting the MAO, an enzyme responsible for destruction of biogenic amines tends to raise the seizure threshold. Serotonin (5-Hydroxy tryptamine) is an inhibitory neuro-transmitter involved in the regulation of mood, sleep, anxiety, arousal and aggression. Serotonin agonists, precursors and neuronal uptake inhibitors are reported to enhance narcoleptic catalepsy. The increase in the serotonergic transmission raises the threshold of PTZ induced seizures in many animal test systems, thereby protecting against PTZ induced convulsions. Dopamine activation seems to be crucial with respect to a lasting internal encoding of motor skills. Dopamine is also believed to provide a teaching signal to parts of brain responsible for acquiring new behavior. In insects, a similar effect has been demonstrated with respect to octopamine, a chemical relative of dopamine. These effects are mediated by dopminergic receptors situated in several parts of brain including substantia nigra. Noradrenaline has also a role to play in the control of seizures, but less significantly when compared with other biogenic amines, as it is mainly concerned with BP regulation. It has a potential for biphasic effect of glutamate in the cerebellum and would inhibit glutamate release at low concentrations. Over activation of glutamate receptors may lead to delayed neuro degeneration as a result of increased influx of calcium ions into neurons. The well-established drugs like phenytoin, carbamazepine and BDZs exerts their action by inhibiting Ca2+ calmodulin stimulated protein phosphorylation in presynaptic nerve terminal. A low concentration of dopamine in cerebellum also has an inhibitory effect on glutamate. Inhibition of prostaglandin synthesis is reported to increase the brain levels of dopamine and noradrenaline, which also causes an inhibition of seizure activity (Balamurugan et al., 2009).
There is an increasing interest in the health risks related to the use of herbal remedies. Although most consumers think that phytomedicines are safe and without side effects, interactions between complementary alternative and conventional medicines are being described. Due to the increase in herbal product self-medication, the use of herbal remedies should be registered while taking the personal clinical history. With the introduction of allopathic drugs, the use of crude drugs from medicinal plants is on the decline and subsequently this traditional knowledge may be lost in the near future. Many drugs that increase the brain content of GABA have exhibited anti-convulsant activity against seizure induced by MES, PTZ and lithium Pilocarpine. The MES is probably the best validated method for assessment of anti-epileptic drugs in generalized tonic clonic seizures. 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 for better control, which in turn increases the chances of drug-drug interaction and side effects. The reports of possible mechanism of action have shown that the identification of particular fraction and or active constituent can further providemore 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 TM 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.