Plants with anticonvulsant properties: a review

Uma revisão de plantas com propriedades anticonvulsivantes

REVISÃO

Plants with anticonvulsant properties - a review

Uma revisão de plantas com propriedades anticonvulsivantes

Lucindo J. Quintans Júnior^{I, *}; Jackson R.G.S. Almeida^II; Julianeli T. Lima^II; Xirley P. Nunes^II; Jullyana S. Siqueira^I; Leandra Eugênia Gomes de Oliveira^III; Reinaldo N. Almeida^III; Petrônio F. de Athayde-Filho^III; José M. Barbosa-Filho^III

^IDepartamento de Fisiologia, Universidade Federal de Sergipe, Campus Universitário "Prof. Aloísio de Campos", 49100-000 São Cristóvão-SE, Brazil

^IILaboratório de Pesquisa do Vale do São Francisco, Universidade Federal do Vale do São Francisco, Caixa Postal 252, 56306-410 Petrolina-PE, Brazil

^IIILaboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, Caixa Postal 5009, 58051-970 João Pessoa-PB, Brazil

ABSTRACT

Seizures are resistant to treatment with currently available anticonvulsant drugs in about 1 out of 3 patients with epilepsy. Thus, there is a need for new, more effective anticonvulsant drugs for intractable epilepsy. However, nature is a rich source of biological and chemical diversity and a number of plants in the world have been used in traditional medicine remedies, i.e., anticonvulsant, anxiolytic, analgesic, antidepressant. This work constitutes a literature review on medicinal plants showing anticonvulsant properties. The review refers to 16 Brazilian plants and a total 355 species, their families, geographical distribution, the utilized parts, method and references. Some aspects of research on medicinal plants and a brief review of the most common animal models to discover antiepileptic drugs are discussed. For this purpose over 170 references were consulted.

Keywords: Medicinal plants, Natural products, convulsion, anticonvulsant properties, animal models, review.

RESUMO

Cerca de um terço dos pacientes epilépticos não conseguem ter um tratamento adequado com as drogas anticonvulsivantes atuais. Nesse sentido, as plantas medicinais surgem como uma fonte promissora de novas moléculas químicas com propriedades biológicas apreciáveis. Muitas plantas ou produtos de origem naturais têm sido propostos para o tratamento de várias patologias, tais como: epilepsia, diabetes, ansiedade, depressão, dentre outras. O presente trabalho realizou um extenso levantamento na literatura especializada de plantas medicinais com propriedades anticonvulsivantes. Um total de 355 espécies vegetais foi identificado, sendo 16 plantas encontradas na flora brasileira, com indicação para o tratamento de quadros convulsivos. Características como nome da espécie, família, partes utilizadas, país do estudo e /ou publicação, métodos e referências foram sumarizados. Além disso, os principais apectos dos modelos animais mais utilizados no estudo de plantas/substâncias com propriedades anticonvulsivantes foram revisados. Mais de 170 referências foram consultadas.

Unitermos: Plantas medicinais, Produtos naturais, convulsão, atividade anticonvulsivante, modelos animais, revisão.

INTRODUCTION

Epilepsy is one of the most common diseases of the brain, affecting at least 50 million persons worldwide (Scheuer & Pedley, 1990). Epilepsy is a chronic and often progressive disorder characterized by the periodic and unpredictable occurrence of epileptic seizures which are caused by an abnormal discharge of cerebral neurons. Many different types of seizures can be identified on the basis of their clinical phenomena (Löscher, 1998). Seizures are fundamentally divided into two major groups: partial and generalized. Partial (focal, local) seizures are those in which clinical or electrographic evidence exists to suggest that the attacks have a localized onset in the brain, usually in a portion of one hemisphere, while generalized seizures are those in which evidence for a localized onset is lacking. Partial seizures are further subdivided into simple partial, complex partial and partial seizures evolving to secondarily generalized seizures, while generalized seizures are categorized into absence (nonconvulsive), myoclonic, clonic, tonic, tonic-clonic and atonic seizures. In addition to classifying the seizures that occur in patients with epilepsy, patients are classified into appropriate types of epilepsy or epileptic syndromes characterized by different seizure types, etiologies, ages of onset and electroencephalographic (EEG) features (Commission, 2003).

The discovery of novel antiepileptic drugs (AEDs) relies upon the preclinical employment of animal models to establish efficacy and safety prior to the introduction of the AEDs in human volunteers (Löscher & Schmidt, 2006). Clearly, the more predictive the animal model for any given seizure type or syndrome, the greater the likelihood that an investigational AED will demonstrate efficacy in human clinical trials (Smith et al., 2007).

Mind-altering drugs, especially plants, have always fascinated human beings. Surrounded by mystic superstitions, magic thoughts and religious rituals, they have always occupied man's attention. Among the plants used by humans, those able to alter the conscience and the sensorium have drawn special consideration. However, the challenge of trying to unravel the mechanisms of action on mood, humor, cognition, ensorium, etc., led to an inconvenience: to ignore, or to face as low priority, the fact that plants could also have beneficial properties to treat mental disease and some psychic ailments (Carlini, 2003; Carlini et al., 2006).

Furthermore, as most of the plants were first used by the so-called primitive cultures, their occasional use by the White occidental culture was relegated to a second plan, being considered as sorcerer's therapeutics. Until recently, very little attention was given by the scientific community to the benefits, as accepted by folk medicine and the medicinal properties of the natural product (Barbosa-Filho et al., 2006a). In addition, nature is a rich source of biological and chemical diversity. The unique and complex structures of natural products cannot be obtained easily by chemical synthesis. A number of plants in the world have been used in traditional medicine remedies (Barbosa-Filho et al., 2006b; Funke & Melzig, 2006; Saúde-Guimarães & Faria, 2007; Agra et al., 2007 and 2008; Veiga-Junior, 2008).

Thus, many plants were known for their anticonvulsant activity. Various phytochemical and pharmacological studies have been carried out on these anticonvulsant plants (Chauhan et al., 1988; Nsour et al., 2000).

In a previous paper this research group has reviewed crude plant extracts and chemically defined molecules with potential antitumor activity for mammary (Moura et al., 2001), cervical (Moura et al., 2002) and ovarian neoplasias (Silva et al., 2003), as inhibitors of HMG CoA reductase (Gonçalves et al., 2000), central analgesic activity (Almeida et al., 2001), employed in prevention of osteoporosis (Pereira et al., 2002), for the treatment of Parkinson's disease (Morais et al., 2003), with antileishmanial (Rocha et al., 2005), hypoglycemic (Barbosa-Filho et al., 2005), and antiinflammatory activity (Falcão et al., 2005, Barbosa-Filho et al., 2006c), inhibitors of the enzyme acetylcholinesterase (Barbosa-Filho et al., 2006a), inhibitors of the angiotensin converting enzymes (Barbosa-Filho et al., 2006b), giardicidal (Amaral et al., 2006), and antileprotic activity (Barbosa-Filho et al., 2007).

The aim of this article is to given an up-to-date review on plants with anticonvulsant properties and realized a brief review of the most common animal models to discover antiepileptic drugs.

MATERIAL AND METHODS

The keywords used for this review were Epilepsy, Plants, Animal models, Anticonvulsant, Natural product and antiepileptic. The search perfound using Chemical Abstracts, Biological Abstracts, Web of Science, ScienceDirect and the data bank of the University of Illinois at Chicago, NAPRALERT (Acronym for NAtural PRoducts ALERT), updated to December 2006. From the literature search, all plants/herbal preparations that are used ethnomedically to treat epilepsy or those which have been tested for anticonvulsant activity are included in this review. The references obtained were later consulted.

RESULTS AND DISCUSSION

Over 170 references were found in which plants have been tested for their anticonvulsant activity in in vivo/in vitro studies or clinical studies. Review refers to 355 species, their families, geographical distribution, the utilized parts and methods (see Table 1).

The 20th century has witnessed considerable progress in anticonvulsant drug development (Loscher & Schmidt, 1994). The major drugs in clinical use, i.e. phenytoin, carbamazepine, valproate, benzodiazepines, ethosuximide, phenobarbital and primidone, were developed and introduced between 1910 and 1970 and will be referred to as 'old drugs' or 'first generation' drugs in the following. After a hiatus of over 20 years, several new anticonvulsant drugs, i.e., vigabatrin, gabapentin, felbamate, lamotrigine, oxcarbazepine, tiagabine and topiramate, have been introduced into clinical practice, referred to as 'new drugs' or 'second generation' drugs in the following. More recent anticonvulsants which are in preclinical or clinical development will be referred to as 'third generation' drugs (Löscher, 1998).

In the other hand, approximately 70% of patients with epilepsy are well controlled by monotherapy with currently available antiepileptic drugs. Another 5-10% of patients are stabilized by the addition of another antiepileptic drug but there remains over 20% of patients whose seizures are not controlled (Richens & Perucca, 1993). Therefore, phytomedicines can potentially play an important role in the development of new antiepileptic drugs to pharmacoresistent patients (Nsour et al., 2000).

Many plants were known for their anticonvulsant activity. Reviews articles (Athanassova et al., 1965 and 1969; Dhar et al., 1968 and 1973; Adesina, 1982a; Chauhan et al., 1988 and Nsour et al., 2000) were previously published with regards to plants with anticonvulsant properties.

In fact, current world-wide interest in traditional medicine has led to rapid development and studies of many remedies employed by various ethnic groups of the world. The information is recorded in alphabetical order of plant scientific name, family, part used, route of administration, dose, method and reference, as showed in Table 1 that summary of the plants which have been tested or reported for anticonvulsant properties.

Among those medicinal plants are found to possess anticonvulsant activity in animal models and/or folk medicine, include: Abelmoschus angulosus, Allium sativum, Artemisia spp, Cannabis sativa, Cinchona officinalis, Egletes viscosa, Icacina trichantha, Magnolia grandiflora, Plumbago zeylanica and others. However, a recent study with Brazilian Northeastern plants showed proexcellent results for the species Bauhinia outimouta, Rauvolfia ligustrina and Ximenia americana (Quintans-Júnior et al., 2002). In our review 13 Brazilian plants were cited: Acosmium subelegans, Artemisia verlotorum, Centella asiatica, Cymbopogon citratus, Erythrina velutina, Erythrina mulungu, Hippeastrum vittatum, Lanata microphylla, Licaria puchury-major, Lippia alba, Nepeta cataria, Passiflora alata and Xylopia spp.

Among those plants tested, a number of them (from different families) are found to possess anticonvulsant activity. While in most cases, the active constituents are yet to be found, for those where the active components are known, they belong to different chemical classes. However, previous studies showed that some natural plant coumarins and triterpenoids exhibit anticonvulsant properties (Chaturvedi et al., 1974; Nsour et al., 2000).

In addition, the history of drug discovery showed that plants are highly rich sources in the search for new active compounds and they have become a challenge to modern pharmaceutical industry. Many synthetic drugs owe their origin to plant-based complementary medicine (Howes et al., 2003; Orhan et al., 2004).

A number of animal models have demonstrated utility in the search for more efficacious and more tolerable AEDs. In fact, the models employed in the early phase of AED discovery are highly predictive of subsequent efficacy in easy-to-manage generalized and partial epilepsy (Smith et al., 2007). Thus, animal models more employed were leptazole-induced seizure (LIS), maximal electroshock seizure (MES), metrazole-induced seizures (MIS), picrotoxin-induced convulsions (PIC), pilocarpine (PILO), pentylenetetrazole (PTZ) and strychnine-induced seizures (SIS). However, MES, PIC and PTZ seizure models continue to represent the three most widely used animal seizure models employed in the search for new AEDs (While et al., 2002).

This review only briefly mention the most common animal methods for evaluating of the plants with anticonvulsant properties and medicinal plants studies to epilepsy described in literature. More information, seen an excellence reviews by Mello et al. (1986), Fisher (1989), Meldrum (1997), Nsour et al. (2000) and Smith et al. (2007).

Animals models for testing anticonvulsant drugs (Screening)

Since the Landmark identification of the anticonvulsant properties of phenytoin in 1936 by virtue of its ability to protect against electroshock-induced convulsions in the cat (Putman & Merritt, 1937) the majority of novel AEDs have been identified through screening in animal models of epilepsy.

The National Institutes of Health (NIH)/American Epilepsy Society (AES) Models II Workshop, held in 2002, described the "ideal" epilepsy model as one that reflects similar pathophysiology and phenomenology to human epilepsy. Seizures should evolve spontaneousl after a postinsult latent period or in a developmental time frame consistent with the human condition. Furthermore, the ideal model should display a pharmacological profile that is resistant to at least two of the existing AEDs (Stables et al., 2003). Finally, the ideal model would be amenable to high-throughput screening. Given the highly heterogeneous nature of seizure disorders in humans, the complexity of the seizure phenotypes, and the syndromes involved, the reality is that it is highly unlikely that any one animal model will ever predict the full therapeutic potential of an investigational AED. Therefore, investigational AEDs are currently evaluated in a battery of syndrome-specific model systems. As specific models are developed (and the drugs they identify are validated clinically), they are integrated into the existing discovery process to better identify more effective antiseizure and potentially antiepileptic therapies. Moving beyond the symptomatic treatment of epilepsy, the goal of most basic and clinical scientists in epilepsy research is to identify therapies capable of preventing, delaying, or modifying the disorder (Smith et al., 2007).

The fact that preclinical models used for identification and development of novel drugs have been originally validated by 'old' drugs, i.e. conventional anticonvulsants, may explain that several of the new drugs possess mechanisms which do not differ from those of the standard drugs .

The MES and PTZ tests

The most commonly employed animal models in the search for new anticonvulsant drugs are the maximal electroshock seizure (MES) test and the pentylenetetrazole (PTZ) seizure test (Löscher & Schmidt, 1988). The maximal electroshock seizure test, in which tonic hindlimb seizures are induced by bilateral corneal or transauricular electrical stimulation, is thought to be predictive of anticonvulsant drug efficacy against generalized tonic-clonic seizures, while the pentylenetetrazole test, in which generalized myoclonic and clonic seizures are induced by systemic (usually s.c. or i.p.) administration of convulsant doses of PTZ, is thought to represent a valid model for generalized absence and/or myoclonic seizures in humans (Löscher, 1998).

Everett and Richards (1944) demonstrated that both trimethadione and phenobarbital, but not phenytoin (PHT), were able to block seizures induced by the GABA_A-receptor antagonist PTZ. Soon thereafter, Lennox (1945) demonstrated that trimethadione was effective at attenuating petit mal (i.e., absence epilepsy) attacks but was ineffective intreating or worsening grand mal seizures (i.e., generalized tonic-clonic seizures).

The positive results obtained in the PTZ seizure test were historically considered suggestive of potential clinical utility against generalized absence epilepsy, based largely on the finding that drugs active in the clinic against spike-wave seizures (e.g., ethosuximide, trimethadione, valproic acid, the benzodiazepines) were effective at blocking clonic seizures induced by PTZ (Smith et al., 2007).

MES and PTZ tests provide some insight into the ability of a given drug to penetrate the blood-brain barrier and exert a central nervous system (CNS) effect. Indeed, both models are nonselective with respect to mechanism and therefore are well suited for screening anticonvulsant activity, as neither model assumes that the pharmacodynamic activity of a particular drug is dependent on its molecular mechanism of action (Smith et al., 2007).

The pilocarpine (PILO) and kainate (KAI) test

Pilocarpine and kainate models replicate several phenomenological features of human temporal lobe epilepsy and can be used as animal preparations to understand the basic mechanisms of epileptogenesis (Turski et al., 1983; Ben-Ari, 1985; Turski et al., 1989). Local or systemic administration of PILO and KAI in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, which can last for several hours (Cavalheiro et al., 1982; Leite et al., 2002).

The brain damage induced by status epilepticus in such preparations may be considered an equivalent of the initial precipitating injury event, usually a prolonged febrile convulsion, which is commonly found in patients with mesial temporal lobe epilepsy (Leite et al., 2002).

Indeed, neuropathological changes such as neuron loss in several hippocampal subfields and reorganization of mossy fibers into the molecular layer of the fascia dentata are observed in both models and are similar to hippocampi from patients with hippocampal sclerosis (Mello et al., 1993; Mathern et al., 1995). This abnormal synaptic reorganization has been suggested to be an anatomical substrate for epileptogenesis (Buckmaster & Dudek, 1997).

Thus, for AED studies in PILO and KAI models, sequential analysis will enable to build precise and reliable correlations between pharmacological effects on seizure behavior and involved brain substrates (Leite et al., 2002).

Chemical kindling model

Those animal models previously cited are convenient but does not mimic spontaneous seizures occurring in the epileptic brain (Meldrum & Rogawski, 2007). Indeed, kindling model has been widely studied both as a tool for understanding chronic epileptogenesis and as a model for testing AEDs with a potential for treating complex partial seizures. This model is too laborious for use as a primary screening procedure, yet it is clear that it consistently identifies compounds with therapeutic potential in complex partial seizures (Löscher & Schmidt, 2006).

The kindling model of epileptogenesis, originally described by Goddard et al. (1969), is characterized by the development of persistent reduction in seizures threshold after a repeated administration of subconvulsant doses of stimulant drugs, such as cocaine, carbamylcholine and pentylenetetrazole (PTZ) (Fabisiak & Schwark, 1982). A well-established model in epilepsy research is PTZ-kindling of mice and rats.

PTZ may cause seizures by inhibitory chloride ion channel associated with GABA_A receptors (Meldrum & Nilsson, 1976). The mechanism underlying kindling are nowadays still not completely understood (Rössler et al., 2000). As PTZ has been shown to interact with the GABA neurotransmitter and the GABA receptor complex (Löscher & Schmidt, 1988), On the other hand, investigations concerning the biochemistry of glutamate, especially modifications in glutamate binding after electrical kindling, showed increased glutamate release and increased receptor density in target neurons populations (Cincotta et al., 1991). Other studies provided evidence that AMPA and NMDA receptors are involved in the initiation of seizures and their propagation (Velisek et al., 1995) and that NMDA receptors antagonists retard the development of kindling (Becker et al., 2001). Although, little is known about the changes of the glutamatergic neuronal transmission after chemical kindling induced by repeated applications of initially subconvulsive doses of PTZ (Rauca et al., 2000), however, alters in glutamatergic system may not be the main factor but one of several possibilities.

Others methods

Summary of the common methods used to evaluation anticonvulsant properties of the medicinal plants and AED as showed in Table 2.

In fact, all currently available drugs are anticonvulsant (anti-seizure) rather than antiepileptic. The latter term should only be used for drugs which prevent or treat epilepsy and not solely its symptoms. The goal of therapy with an anticonvulsant drug is to keep the patient free of seizures without interfering with normal brain function (Löscher, 1998). The selection of an anticonvulsant drug is based primarily on its efficacy for specific types of seizures and epilepsy (Mattson, 1995).

CONCLUSION

It can be concluded that studies with species from a range of families have been shown anticonvulsant properties and understanding of the complex mechanism of epilepsy. Academic institutions should invest in this type of study with medicinal plants and contribute to the benefit of the populations needing this type of health care. Thus, it is the wish of the authors that this review article will stimulate the interests in further investigations into natural products for new antiepileptic agents.

Received 1 October 2008

5 November 2008

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Publication Dates

• Publication in this collection
  09 Mar 2009
• Date of issue
  Dec 2008

History

• Accepted
  05 Nov 2008
• Received
  01 Oct 2008