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Revista Brasileira de Farmacognosia

Print version ISSN 0102-695XOn-line version ISSN 1981-528X

Rev. bras. farmacogn. vol.18  suppl.0 João Pessoa Dec. 2008

http://dx.doi.org/10.1590/S0102-695X2008000500026 

REVISÃO

 

Plants with anticonvulsant properties - a review

 

Uma revisão de plantas com propriedades anticonvulsivantes

 

 

Lucindo J. Quintans JúniorI, *; Jackson R.G.S. AlmeidaII; Julianeli T. LimaII; Xirley P. NunesII; Jullyana S. SiqueiraI; Leandra Eugênia Gomes de OliveiraIII; Reinaldo N. AlmeidaIII; Petrônio F. de Athayde-FilhoIII; José M. Barbosa-FilhoIII

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 GABAA-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 GABAA 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.

 

REFERENCES

Abdul-Ghani AS, El-Lati SG, Sacaan AI, Suleiman MS, Amin RM 1987. Anticonvulsant effects of some Arab medicinal plants. Int J Crude Drug Res 25: 39-43.         [ Links ]

Abila B, Richens A, Davies JA 1993. Anticonvulsant effects of extracts of the West African black pepper, Piper guineense. J Ethnopharmacol 39: 113-117.         [ Links ]

Adesina SK, Sofowora EA 1979. The isolation of an anticonvulsant glycoside from Tetrapleura tetraptera. Planta Med 36: 270-271.         [ Links ]

Adesina SK 1982a. Studies on some plants used as anticonvulsants in Amerindian and African traditional medicine. Fitoterapia 53: 147-162.         [ Links ]

Adesina SK, Ette EI 1982b. The isolation and identification of anticonvulsant agents from Clausena anisata and Afraegle paniculata. Fitoterapia 53: 63-66.         [ Links ]

Agra MF, França PF, Barbosa-Filho JM 2007. Synopsis of the plants known as medicinal and poisonous in Northeast of Brazil. Rev Bras Farmacogn 17: 114-140.         [ Links ]

Agra MF, Silva KN, Basílio IJLD, França PF, Barbosa-Filho JM 2008. Survey of medicinal plants used in the region Northeast of Brazil. Rev Bras Farmacogn 18: 472-508.         [ Links ]

Aguilar-Santamaria L, Tortoriello J 1996. Anticonvulsant and sedative effects of crude extracts of Ternstroemia pringlei and Ruta chalepensis. Phytother Res 10: 531-533.         [ Links ]

Ahmad M, Tariq M, Afaq SH, Asif M 1981. A pharmacological study on udesaleeb (Paeonia emodi Linn.): a unani anticonvulsant drug. Bull Islamic Med 1: 444-447.         [ Links ]

Aji BM, Onyeyili PA, Osunkmo UA. 2001. The central nervous effects of Mitragyna africanus (Willd) stembark extract in rats. J Ethnopharmacol 77: 143-149.         [ Links ]

Akah PA, Nwaiwu JI 1988. Anticonvulsant activity of root and stem extracts of Calliandra portoricensis. J Ethnopharmacol 22: 205-210.         [ Links ]

Akah PA, Nwambie AI 1993. Nigerian plants with anti-convulsant property. Fitoterapia 64: 42-44.         [ Links ]

Akah PA, Nwambie AI, Gamaniel KS, Wambebe C 1997. Experimental study of the anticonvulsant used for treatment of infantile convulsion in Nigeria. Brain Res Bull 44: 611-613.         [ Links ]

Akbar S, Nisa M, Tariq M. 1985a. A study on CNS depressant activity of Salvia haematodes Wall. Int J Crude Drug Res 22: 41-44.         [ Links ]

Akbar S, Nisa M, Tariq M 1985b. CNS depressant activity of Cuscuta chinensis Lamm. Int J Crude Drug Res 23: 91-94.         [ Links ]

Aksenova RA, Zotov MI, Nekhoda MF, Cherdyntsev SG 1966. Stimulating and adaptogenic effects of a refined preparation of Rhodiola rosea Rhodosin. Stimulyatory Tsent Nerv Sist (Ed:Saratikov As) Izd Tomsk Univ Tomsk 77.         [ Links ]

Almeida RN, Navarro DS, Barbosa-Filho JM 2001. Plants with central analgesic activity. Phytomedicine 8: 310-322.         [ Links ]

Amabeoku GJ, Leng MJ, Syce MA 1998. Antimicrobial and anticonvulsant activites of Viscum capense. J Ethnopharmacol 61: 237-241.         [ Links ]

Amabeoku GJ, Green I, Kabatende J 2007. Anticonvulsant activity of Cotyledon orbiculata L. (Crassulaceae) leaf extract in mice. J Ethnopharmacol 112: 101-107.         [ Links ]

Amaral FMM, Ribeiro MNS, Barbosa-Filho JM, Reis AS, Nascimento FRF, Macedo RO 2006. Plants and chemical constituents with giardicidal activity. Rev Bras Farmacogn 16 (Supl.): 696-720.         [ Links ]

Ameri A 1997. Inhibition of rat hippocampal excitability by the Aconitum alkaloid, 1-benzoylnapelline, but not by napelline. Eur J Pharmacol 335: 145-152.         [ Links ]

Ansari SH, Ali M, Qadry JS 1993. Essential oils of Pistacia integerrima galls and their effect on the central nervous system. Int J Pharmacogn 31: 89-95.         [ Links ]

Arunlakshana C 1949. Pharmacological study of the leaves of Cassia siamea. Siriraj Hosp Gaz 1: 434-444.         [ Links ]

Asuzu IU 1986. Pharmacological evaluation of the folklore use of Sphenostylis stenocarpa. J Ethnopharmacol 16: 263-267.         [ Links ]

Asuzu IU, Ugwueze EE 1990. Screening of Icacina trichantha extracts for pharmacological activity. J Ethnopharmacol 28: 151-156.         [ Links ]

Athanassova S, Shopova S, Roussinov K 1965. Pharmacological studies of Bulgarian plants with a view to their anti-convulsive effect. Acad Bulg Sci 18: 691-694.         [ Links ]

Athanassova S, Shopova S, Roussinov K, Markova M 1969. Pharmacological studies of Bulgarian plants with a view to their anticonvulsive effect. Izv Inst Fiziol Bulg Akad Nauk 12: 205-216.         [ Links ]

Awe SO, Olajide OA, Adeboye JO, Makinde JM 1997. Pharmacological evaluation of Khaya grandifoliola methanolic extract. J Pharm Res Dev 2: 20-23.         [ Links ]

Bac P, Pages N, Dhalluin S, Tapiero H 1998. Protective effect of Crassostrea gigas extract on audiogenic seizures in magnesium deficient mice. Biomed Pharmacother 52: 162-165.         [ Links ]

Baek NI, Han JT, Ahn EM, Park JK, Cho SW, Jeon SG, Jang JS, Kim CK, Choi SY 2000. Isolation of anticonvulsant compounds from the fruits of Schizandra chinensis Baili. Han'guk Nonghwa Hakhoe Chi 43: 72-77.         [ Links ]

Baird-Lambert J, Dunlop RW, Jamieson DD 1980. Anticonvulsant activity of a novel diterpene isolated from a soft coral of Thegenus lobophytum. Arzneim-Forsch 30: 964-967.         [ Links ]

Barbosa-Filho JM, Vasconcelos THC, Alencar AA, Batista LM, Oliveira RAG, Guedes DN, Falcão HS, Moura MD, Diniz MFFM, Modesto-Filho J 2005. Plants and their active constituents from South, Central, and North America with hypoglycemic activity. Rev Bras Farmacogn 15: 392-413.         [ Links ]

Barbosa-Filho JM, Medeiros KCP, Diniz MFFM, Batista LM, Athayde-Filho PF, Silva MS, Cunha EVL, Almeida JRGS, Quintans-Júnior LJ 2006a. Natural products inhibitors of the enzyme acetylcholinesterase. Rev Bras Farmacogn 16: 258-285.         [ Links ]

Barbosa-Filho JM, Martins VKM, Rabelo LA, Moura MD, Silva MS, Cunha EVL, Souza MFV, Almeida RN, Medeiros IA 2006b. Natural products inhibitors of the angiotensin converting enzyme (ACE). A review between 1980-2000. Rev Bras Farmacogn 16: 421- 446.         [ Links ]

Barbosa-Filho JM, Piuvezam MR, Moura MD, Silva MS, Lima KVB, Cunha EVL, Fechine IM, Takemura OS 2006c. Anti-inflammatory activity of alkaloids: A twenty-century review. Rev Bras Farmacogn 16: 109-139.         [ Links ]

Barbosa-Filho JM, Nascimento-Júnior FA, Tomaz ACA, Athayde-Filho PF, Silva MS, Cunha EVL, Souza MFV, Batista LM, Diniz MFFM 2007. Natural products with antileprotic activity. Rev Bras Farmacogn 17: 141-148.         [ Links ]

Barros Viana GS, Vale TGD, Silva CMM, Abreu Matos FJ 2000. Anticonvulsant activity of essential oils and active principles from chemotypes of Lippia alba (Mill.). Biol Pharm Bull 23: 1314-1317.         [ Links ]

Becker A, Grecksch G, Schröeder H 2001. Low doses of AMPA exert anticonvulsant effects on pentylenetetrazol-kindled seizures. Pharmacol Biochem Behav 70: 421-426.         [ Links ]

Beinvenu E, Amabeoku GJ, Eagles PK, Scott G, Springfield EP 2002. Anticonvulsant activity of aqueous extract of Leonotis leonurus. Phytomedicine 217: 217-223.         [ Links ]

Ben-Ari Y 1985. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14: 375-403.         [ Links ]

Bernardi MM, Souza-Spinosa H, Batatinha MJM, Giorgi R 1991. Croton zehntneri: possible central nervous system effects in rodents. J Ethnopharmacol 33: 285-287.         [ Links ]

Bhakuni OS, Dhar ML, Dhar MM, Dhawan BN, Mehrotra BN 1969. Screening of Indian plants for biological activity. Part II. Indian J Exp Biol 7: 250-262.         [ Links ]

Bhakuni DS, Dhar ML, Dhar MM, Dhawan BN, Gupta B, Srimali RC 1971. Screening of indian plants for biological activity. Part III. Indian J Exp Biol 9: 91.         [ Links ]

Bhakuni DS, Goel AK, Jain S, Mehrotra BN, Patnaik GK, Prakash V 1988. Screening of indian plants for biological activity. Indian J Exp Biol 26: 883-904.         [ Links ]

Bhattacharya SK, Debnath PK, Pandey VB, Sanyal AK 1975. Pharmacological investigations on Elaeocarpus ganitrus. Planta Med 28: 174-177.         [ Links ]

Buckmaster PS, Dudek FE 1997. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J Comput Neurol 385: 385-404.         [ Links ]

Buznego MT, Perez-Saad H 1999. Efecto antiepileptico de Plectranthus amboinicus (Lour.) Spreng. (oregano frances). Rev Neurol 28: 388-392.         [ Links ]

Carlini EA, Oliveira AB, Oliveira GG 1983. Psychopharmacological effects of the essential oil fraction ando f the hydrolate obtained from the seeds of Licaria puchury-major. J Ethnopharmacol 8: 224-236.         [ Links ]

Carlini EA, Contar JDP, Silva-Filho AR, Silveira NGD, Frochtengarten ML, Bueno OFA 1986. Pharmacology of lemongrass (Cymbopogon citratus Starpf). I. Effects of teas prepared from the leaves on laboratory animals. J Ethnopharmacol 17: 37-64.         [ Links ]

Carlini EA 2003. Plants and the central nervous system. Pharmacol Biochem Behav 75: 501-512.         [ Links ]

Carlini EA, Rodrigues E, Mendes FR, Tabach R, Gianfratti B 2006. Treatment of drug dependence with Brazilian herbal medicines. Rev Bras Farmacogn 16: 690-695.         [ Links ]

Cavalheiro EA, Riche DA, Le Gal La Salle G 1982. Long-term effects of intrahippocampal kainic acid injection in rats: a method for nducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol 53: 581-589.         [ Links ]

Chatterjee C 1964. Pharmacological screening of Valeriana wallichi DC, Lallermentia royleana Benth, Breynia rhamnoides Muell-Arg and Evolvulus numularians for sedative and anticonvulsive principles. Naturwissenschaften 51: 411.         [ Links ]

Chaturvedi AK, Parmar SS, Bhatnagar SC, Misra G, Nigam SK 1974. Anticonvulsant and anti-inflammatory activity of natural plant coumarins and triterpenoids. Res Commun Chem Path 9: 11-22.         [ Links ]

Chauhan AK, Dobhal MP, Joshi B 1988. A review of medicinal plants showing anticonvulsant activity. J Ethnopharmacol 22: 11-23.         [ Links ]

Chen HY 1977. Studies on tien-ma and huan-jun,the pharmacological effects of tien-ma decoction, and mi-huan-jun fermentation product on the central nervous system. Chung-Hua I Hsueh Tsa Chih (Beijing) 57: 470-472.         [ Links ]

Chermat R, Lachapelle F, Baumann N, Simon P 1979. Anticonvulsant effect of yohimbine in quaking mice: antagonism by clonidine and prazosine. Life Sci 25: 1471-1476.         [ Links ]

Chiou LC, Ling JY, Chang CC 1997. Chinese herb constituent beta-eudesmol alleviated the electroshock seizures in mice and electrographic seizures in rat hippocampal slices. Neurosci Lett 231: 171-174.         [ Links ]

Cincotta M, Young NA, Beart PM 1991. Unilateral up-regulation of glutamate receptors in limbic regions of amygdaloid-kindled rats. Exp Brain Res 85: 650-658.         [ Links ]

Commission on Classification and Terminology of the International League Against Epilepsy. 2003. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30: 389-399.         [ Links ]

Contreras CM, Chacon L, Enriquez RG 1996. Anticonvulsant properties of Ipomoea stans. Phytomedicine 3: 41-44.         [ Links ]

Czarnecki R, Librowski T, Zebala K, Kohlmunzer S 1993. Pharmacological properties of a lyophilizate from Galeopsis ladanum on the central nervous system of rodents. Phytother Res 7: 9-12.         [ Links ]

Dantas FG 2005. Epilepsy and Marijuana - A Review. J Epilepsy Clin Neurophysiol 11: 91-93.         [ Links ]

Das PK, Nath V, Gode KD, Sanyal AK 1964. Preliminary phytochemical and pharmacological studies on Cocculus hirsutus Linn. Indian J Med Res 52: 300-307.         [ Links ]

Dasgupta A, Agarwal SS, Basu DK 1984. Anticonvulsant activity of the mixed fatty acids of Elaeocarpus ganitrus roxb. (Rudraksh). Indian J Physiol Pharmacol 28: 245-246.         [ Links ]

De Lima TCM, Klueger PA, Pereira PA, Macedo-Neto WP, Morato GS, Farias MR 1998. Behavioural effects of crude and semi-purified extracts of Syzygium cuminii Linn. skeels. Phytother Res 12: 488-493.         [ Links ]

De Lucia R, Sertie JAA, Camargo EA, Panizza S 1997. Pharmacological and toxicological studies on Centella asiatica extract. Fitoterapia 68: 413-416.         [ Links ]

Debelmas AM, Hache J 1976. Toxicity of several medicinal plants of Nepal including some behavioral and central nervous system effects. Plant Med Phytother 10: 128-138.         [ Links ]

Declume C, Assamoi A, Akre TB 1984. Anticonvulsivant activity of Cnestis ferruginea DC., Connaraceae. Ann Pharm Fr 42: 35-41.         [ Links ]

Dey PK, Chatterjee BK 1968. Studies on the neuropharmacological properties of several indian medicinal plants. J Res Indian Med 3: 9-18.         [ Links ]

Dhar ML, Dhar MM, Dhawan BN, Mehrotra BN, Ray C 1968. Screening of Indian plants for biological activity: Part I. Indian J Exp Biol 6: 232-247.         [ Links ]

Dhar ML, Dhar MN, Dhawan BN, Mehrotra BN, Srimal RC, Tandon JS 1973. Screening of Indian plants for biological activity. Part IV. Indian J Exp Biol 11: 43-54.         [ Links ]

Dhawan BN, Patnaik GK, Rastogi RP, Singh KK, Tandon JS 1977. Screening of Indian plants for biological activity. VI. Indian J Exp Biol 15: 208-219.         [ Links ]

Dikshit S, Tewari PV, Dixit SP 1972. Anticonvulsant activity of Canscora decussata Roem. & Sch. Indian J Physiol Pharmacol 16: 81-83.         [ Links ]

Duarte FS, Duzzioni M, Mendes BG, Pizzolatti MG, De Lima TCM 2007. Participation of dihydrostyryl-2-pyrones and styryl-2-pyrones in the central effects of Polygala sabulosa (Polygalaceae), a folk medicine topical anesthetic. Pharmacol Biochem Behav 86: 150-161.         [ Links ]

Dwivedi C, Harbison RD 1975. Anticonvulsant activities of delta-8- and delta-9-tetrahydrocannabinol and uridine. Toxicol Appl Pharmacol 31: 452.         [ Links ]

Everett GM, Richards RK 1944. Comparative anticonvulsive action of 3,5,5-trimethyloxazolidine-2,4-dione (Tridione), dilantin and phenobarbital. J Pharmacol Exp Ther 81: 402-407.         [ Links ]

Fabisiak JP, Schwark WS 1982. Aspects of the pentylenetetrazol kindling model of epileptogenesis in the rat. Exp Neurol 78: 7-14.         [ Links ]

Falcão HS, Lima IO, Santos VL, Dantas HF, Diniz MFFM, Barbosa-Filho JM, Batista LM 2005. Review of the plants with anti-inflammatory activity studied in Brazil. Rev Bras Farmacogn 15: 381-391.         [ Links ]

Fehri B, Aiache JM, Boukef K, Memmi A, Hizaoui B 1991. Valeriana officinalis and Crataegus oxyacantha: reiterated administrations and pharmacological properties. J Pharm Belg 46: 165-176.         [ Links ]

Fisher RS 1989. Animal models of the epilepsies. Brain Res Rev 14: 245-278.         [ Links ]

Fukuda T, Shibata H 1994. Persimmon calyx extracts as anticonvulsants and to alleviate the side effects of barbituric acid compounds. Patent-Japan Kokai Tokkyo Koho 06: 649.         [ Links ]

Funke I, Melzig MF 2006. Traditionally used plants in diabetes therapy - phytotherapeutics as inhibitors of α-amylase activity. Rev Bras Farmacogn 16: 1-5.         [ Links ]

Gilani AH, Aziz N, Khan MA, Shaheen F, Jabeen Q, Siddiqui BS, Herzig JW 2000. Ethnopharmacological evaluation of the anticonvulsant, sedative and antispasmodic activities of Lavandula stoechas L. J Ethnopharmacol 71: 161-167.         [ Links ]

Goddard GV, Mclntyre DC, Leech CK 1969. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25: 295-330.         [ Links ]

Gonçalves MCR, Moura LSA, Rabelo LA, Cruz HMM, Cruz J, Barbosa-Filho JM 2000. Produtos naturais inibidores da enzima HMG CoA redutase. Rev Bras Farm 81: 63-71.         [ Links ]

Gonzalez-Trujano ME, Navarrete A, Reyes B, Hong, E 1998. Some pharmacological effects of the ethanol extract of leaves of Annona diversifolia on the central nervous system in mice. Phytother Res 12: 600-602.         [ Links ]

Guo Q, Kuang P 1993. Effect of Qingyangshen on hippocampal alpha and beta tubulin gene expression during kainic acid induced epileptogenesis. J Trad Chinese Med 14: 281-286.         [ Links ]

Gupta A, Wambebe CO, Parsons DL 1990. Central and cardiovascular effects of the alcoholic extract of the leaves of Carica papaya. Int J Crude Drug Res 28: 257-266.         [ Links ]

Gupta SK, Kharya MD 1996. Phytochemical and pharmacological studies on seeds on Sapindus trifoliatus. Indian J Nat Prod 12: 3-8.         [ Links ]

Gupta M, Mazumder UK, Das S 1998. Effect of leaf extract from Clerodendron colebrookianum on CNS function in mice. Indian J Exp Biol 36: 171-174.         [ Links ]

Haruna AK. 2000. Depressant and anticonvulsant properties of the root decoction of Afrormosia laxiflora (Leguminosae). Phytother Res 14: 57-59.         [ Links ]

Hien TTM, Navarro-Delmasure C, Vy T 1991. Toxicity and effects on the central nervous system of a Cerbera odollam leaf extract. J Ethnopharmacol 34: 201-206.         [ Links ]

Hong ND 1976. Pharmacological studies of Scolopendra subspinipes mutiland koch. Korean J Pharmacogn 7: 99-109.         [ Links ]

Hong ND, Kim CW, Shin HD 1979. A study on the analgesic and anti-convulsional effect of Paeoniae radix. Korean J Pharmacogn 10: 119-124.         [ Links ]

Hong ND, Koo BH, Joo SM, Lee SK 1988. Studies on the efficacy of combined preparation of crude drugs (XXXVI). Effects of Sipmidojuksan on the central nervous and cardiovascular systems. Korean J Pharmacogn 19: 141.         [ Links ]

Howes MJR, Perry NSL, Houghton PJ 2003. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res 17: 1-18.         [ Links ]

Hsieh MT, Peng WH, Yeh FT, Tsai HY, Chang YS 1991. Studies on the anticonvulsive, sedative and hypothermic effects of Periostracum cicadae extracts. J Ethnopharmacol 35: 83-90.         [ Links ]

Hsieh CL, Tang NY, Chiang SY, Hsieh CT, Lin JG 1999. Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (Miq.) Jac and Gastrodia elata Bl., in kainic acid-treated rats. Life Sci 65: 2071-2082.         [ Links ]

Hsieh CL, Chiang SY, Cheng KS, Lin YH, Tang NY, Lee CJ, Pon CZ, Sieh CT 2001. Anticonvulsive and free radical scavenging activities of Gastrodia elata Bl. in kainic acid-treated rats. Amer J Chinese Med 29: 331-341.         [ Links ]

Hu RQ, Davies JA 1997. Effects of Piper nigrum L. on epileptiform activities in cortical wedges prepared from DBA/2 mice. Phytother Res 11: 222-225.         [ Links ]

Hung ND, Chang IK, Jung HC, Kim NJ 1983. Studies on the efficacy of combined preparation of crude drugs (XII). Korean J Pharmacogn 14: 9-16.         [ Links ]

Hyou SY, Que PY, Gao GQ, Zhang YX 2001. The effect of Vernonia gratiosa hance on the locomotor and convulsion activity in mice. J Chin Pharm Sci 2(1): 11-18.         [ Links ]

Junhua H, Dechao Y, Xianyu C, Zemin H, Xiaozhang F, Araki H, Tsuchida K, Asami Y, Aihara H, Watanabe N, Obuchi T, Omura S 1990. Effects of mi huan jun (Armillaria mellea) on central nervous and vascular system. Fitoterapia 61: 207-214.         [ Links ]

Kasahara Y, Hikino H 1987. Central actions of Ganoderma lucidum. Phytother Res 1: 17-21.         [ Links ]

Kasahara Y, Kumaki K, Sato T, Katagiri S 1989. Pharmacological studies on flower petals of Carthamus tinctorius central actions and antiinflammation. Shoyakugaku Zasshi 43: 331-338.         [ Links ]

Kasture VS, Kasture SB, Pal SC 1996. Anticonvulsant activity of Albizzia lebbeck. Indian J Exp Biol 34: 78-80.         [ Links ]

Kasture VS, Chopde CT, Deshmukh VK 2000. Anticonvulsive activity of Albizzia lebbeck, Hibiscus rosa sinesis and Butea monosperma in experimental animals. J Ethnopharmacol 71: 65-75.         [ Links ]

Kasture VS, Chopde CT, Deshmukh VK 2002. Anxiolytic and anticonvulsive activity of Sesbania grandiflora leaves in experimental animals. Phytother Res 16: 455-460.         [ Links ]

Ketusingha A, Arunluk U 1950. Studies of ocimum seeds for food and drug purposes. Shiriraj Hospital Gazette 2: 593-604.         [ Links ]

Kim DY, Choi JW, Park JC, Lee CK 1998. Anticonvulsant effect of Uncariae ramulus et Uncus. II. Effects of methanol extract and ethyl acetate fraction on neurotransmitters related components in brain. Korean J Pharmacogn 29: 179-186.         [ Links ]

Klohs MW, Keller F, Williams RE, Toekes MI, Cronheim GE 1959. A chemical and pharmacological investigation of Piper methysticum Forst. J Med Pharm Chem 1: 103.         [ Links ]

Kuang P, Lang SY, Liu JX, Zhang FY, Wu WP 1991. The investigation of antiepileptic action of Qingyanshen (QYS). J Trad Chinese Med 11: 40-46.         [ Links ]

Kulshrestha VK, Singh N, Saxena RC, Kohli RP 1970. Central pharmacological activity of an alkaloid fraction of Apium graveolens. Indian J Med Res 58: 99-102.         [ Links ]

Kurukawa K, Chairungsrilered N, Ohta T, Nozoe S, Ohizumi Y 1997. Novel types of receptor antagonists from the medicinal plant Garcinia mangostana. Nippon Yakurigaku Zasshi 110: 153-158.         [ Links ]

Laguna MR, Villar RM, Cadavid I, Calleja JM 1990. Effects of Phaeodactylum tricornutum and Dunaliella tertiolecta extracts on the central nervous system. Planta Med 56: 152-157.         [ Links ]

Laguna MR, Villar RM, Cadavid I, Calleja JM 1993. Effects of extracts of Tetraselmis suecica and Isochrysis galbana on the central nervous system. Planta Med 59: 207-214.         [ Links ]

Lanhers MC, Fleurentin J, Dorfman P, Misslin R, Mortier F 1996. Neurophysiological effects of Ruphorbia hirta L. (Euphorbiaceae). Phytother Res 10: 670-676.         [ Links ]

Lashev LD, Droumev DM, Stoianova-Ivanova B 1981. Pharmacological activity of alcohol extracts from the overground parts of Chrysanthemum indicum, parviflorous form. C R. Acad Bulg Sci 34: 1029-1032.         [ Links ]

Lee IR, Kim JS, Lee SH 1992. Pharmacological activities of leaves of Hedera rhombea Bean. Korean J Pharmacogn 23: 34-42.         [ Links ]

Lee KM, Jung JS, Song DK, Krauter M, Kim YH 1993. Effects of Humulus lupulus extract on the central nervous system in mice. Planta Med 59: 691.         [ Links ]

Leite JP, Garcia-Cairasco N, Cavalheiro EA 2002. New insights from the use of pilocarpine and kainate models. Epilepsy Res 50: 93-103.         [ Links ]

Lennox WG 1945. The petit mal epilepsies: their treatment with Tridione. JAMA-J Am Med Assoc 129: 1069-1074.         [ Links ]

Leslie GB 1978. A pharmacometric evaluation of nine bio-strath herbal remedies. Medita 8: 3-19.         [ Links ]

Li GY 1987 Treatment of 278 cases of epilepsy with baili pill. J New Chin Med 19: 33.         [ Links ]

Liao JF, Huang SY, Jan YM, Yu LL, Chen CF 1998. Central inhibitory effects of water extract of Acori gramminei rhizoma in mice. J Ethnopharmacol 61: 185-193.         [ Links ]

Lima TCM, Morato GS, Takahashi RN 1993. Evaluation of the central properties of Artemisia verlotorum. Planta Med 59: 326-329.         [ Links ]

Liu CM, Gao DZ, Yu PY, Zhou XH 1989. Anti-epileptic effect of the venom of Buthus martensii karasch and antiepilepsy peptide. Shenyang Yaoxueyuan Xuebao 6: 95-98.         [ Links ]

Lodge D, Johnston GAR, Curtis DR, Brand SJ 1997. Effects of the Areca nut constituent arecaidine and guvacine on the action of GABA in the cat central nervous system. Brain Res 136: 513-522.         [ Links ]

Löscher W, Schmidt D 1988. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 2: 145-181.         [ Links ]

Löscher W, Schmidt D 1994. Strategies in antiepileptic drug development: Is rational drug design superior to random screening and structural variation? Epilepsy Res 17: 95-134.         [ Links ]

Löscher W 1998. New visions in the pharmacology of anticonvulsion. Eur J Pharmacol 342: 1-13.         [ Links ]

Löscher W, Schmidt D 2006. New horizons in the development of antiepileptic drugs: Innovative strategies. Epilepsy Res 69: 183-272.         [ Links ]

Mahe M, Driessche JV, Girre L 1978. Pharmacological properties of several indigenous plants on the nervous system. Plant Med Phytother 12: 248-258.         [ Links ]

Makanju OOA 1983. Behavioral and anticonvulsant effects of an aqueous extract from the roots of Clausena anisata (Rutaceae). Int J Crude Drug Res 21: 29-32.         [ Links ]

Maklad YA, Aboutabl EA, El-Sherei MM, Meselhy KM 1997. Phytochemical and pharmacological studies of Salvia transsylvaniaca (Schur ex Griseb) grown in Egypt. Bull Fac Pharm Cairo Univ 35: 213-220.         [ Links ]

Mannan A, Khan RA, Asif M 1989. Pharmacodynamic studies on Polypodium vulgare(Linn.). Indian J Exp Biol 27: 556-560.         [ Links ]

Marcus DA, Scharff L, Turk D, Gourley LM 1997. A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia 17: 855-862.         [ Links ]

Massoco CO, Silva MRPR, Gorniak SL, Spinosa HS, Brnardi MM 1995. Behavioral effects of acute and long-term administration of catnip (Nepeta cataria) in mice. Vet Hum Toxicol 37: 530-533.         [ Links ]

Mathern GW, Babb TL, Pretorius JK, Leite JP 1995. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human Fascia dentata. J Neurosci 15: 3990-4004.         [ Links ]

Mattson RH 1995. Selection of antiepileptic drug therapy. In: Levy RH, Mattson RH, Meldrum BS. Eds., Antiepileptic Drugs, 4th ed. Raven Press, New York, pp. 123-136.         [ Links ]

Mazzanti G, Bettschart A, Braghiroli L, Saso L, Panzironi C 1993. Persea indica: general pharmacological effects of the total extract. Pharmacol Res 27: 19-20.         [ Links ]

Mehta C, Gupta U, Srivastava VK, Satyavati GV, Prasad DN 1979. Pharmacological studies on Pterocarpus santalinus Linn (red sanders). J Res Indian Med Yoga Homeopathy 14: 37-43.         [ Links ]

Meldrum BS, Nilsson B 1976. Cerebral blood flow and metabolic rate early and late in prolonged epileptic seizures induced in rats by bicuculline. Brain 99: 523-542.         [ Links ]

Meldrum BS 1997. Identification and preclinical testing of novel antiepileptic compounds. Epilepsia 38: S7-S15.         [ Links ]

Meldrum BS, Rogawski MA 2007. Molecular targets for antiepileptic drug development. Neurotherapeutics. J Am Soc Exp NeuroTher 4: 18-61.         [ Links ]

Mello LE, Bortolotto ZA, Cavalheiro EA 1986. Modelos experimentais de epilepsias. Uma Revisão. Neurobiologia 49: 231-268.         [ Links ]

Mello LE, Cavalheiro EA, Tan AM, Kupfer WR, Pretorius JK, Babb TL, Finch DM 1993. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34: 985-995.         [ Links ]

Mishra P, Agrawal RK 1988. Some pharmacological actions of the essential oil of Luvanga scandens. Fitoterapia 59: 441-448.         [ Links ]

Mishra P, Agrawal RK 1989. Some observations on the pharmacological activities of the essential oil of Junipeerus macropoda. Fitoterapia 60: 339-345.         [ Links ]

Mitra SK, Chakrabori A, Bhattacharya SK 1996. Neuropharmacological studies on Panax ginseng. Indian J Exp Biol 34: 41-47.         [ Links ]

Monforte MT, Trovato A, Rossitto A, Forestieri AM, D'aquino A, Miceli N, Galati EM 2002. Anticonvulsant and sedative effects of Salvadora persica L. stem extracts. Phytother Res 16: 395-397.         [ Links ]

Morais LCSL, Barbosa-Filho JM, Almeida RN 2003. Plants and bioactives compounds for the treatment of Parkinson's desease. Arquivos Brasileiros de Fitomedicina Científica 1: 127-132.         [ Links ]

Moreno L, Bello R, Primo-Yufera E, Esplugues J 2002. Pharmacological properties of the methanol extract from Mentha suaveolens Ehrh. Phytother Res 16: 10-13.         [ Links ]

Moura MD, Torres AR, Oliveira RAG, Diniz MFFM, Barbosa-Filho JM 2001. Natural products inhibitors of models of mammary neoplasia. Brit J Phytotherapy 5: 124-145.         [ Links ]

Moura MD, Silva JS, Oliveira RAG, Diniz MFFM, Barbosa-Filho JM 2002. Natural products reported as potential inhibitors of uterine cervical neoplasia. Acta Farm Bonaerense 21: 67-74.         [ Links ]

Narita Y, Satowa H, Kokubu T, Sugaya E 1982. Treatment of epileptic patients with the chinese herbal medicine 'Saiko-Keishi-To' (SK). Ircs Libr Compend 10: 88-89.         [ Links ]

Ngo Bum E, Meier CL, Urwyler S, Wang Y, Herrling PL 1996. Extracts from rhizomes of Cyperus articulatus (Cyperaceae) displace [3H] CGP39653 and [3H] glycine binding from cortical membranes and selectively inhibit NMDA receptor-mediated neurotransmission. J Ethnopharmacol 54: 103-111.         [ Links ]

N'gouemo P, Nuguemby-Bina C, Baldy-Moulinier M 1994a. Some neuropharmacological effects of an ethanolic extract of Maprounea africanna in rodents. J Ethnopharmacol 43: 161-166.         [ Links ]

N'gouemo P, Baldy-Moulinier M, Nguemby-Bina C 1994b. Some pharmacological effects of an ethanolic extract of Palisota ambigua on the central nervous system in mice. Phytother Res 8: 426-429.         [ Links ]

N'gouemo P, Baldy-Moulinier M, N'guemby-Bina C 1996. Effects of an ethanolic extract of Desmodium adscendens on central nervous system in rodents. J Ethnopharmacol 52: 77-83.         [ Links ]

N'gouemo P, Koudogbo B, Tchivounda HP, Akono-Nguema C, Etoua MM 1997. Effects of ethanol extract of Annona muricata on pentylenetetrazol-induced convulsive seizures in mice. Phytother Res 11: 243-245.         [ Links ]

Nguelefack TB, Nana P, Atsamo AD, Dimo P, Watcho P, Dongmo AD, Tapondjou LA, Njamen D, Wansi SL, Kamanyi A 2006. Analgesic and anticonvulsant effects of extracts from the leaves of Kalanchoe crenata (Andrews) Haworth (Crassulaceae). J Ethnopharmacol 106: 70-75.         [ Links ]

Nikol-Skaya BS, Shreter AI 1961. Tincture of Cimicifuga dahurica. Med Prom SSSR 15: 47.         [ Links ]

Nogueira E, Vassilieff VS 2000. Hypnotic, anticonvulsant and muscle relaxant effects of Rubus brasiliensis. involvement of GABAA system. J Ethnopharmacol 70: 275-280.         [ Links ]

Nsour WN, Lau CBS, Wong ICK 2000. Review on phytotherapy in epilepsy. Seizure 9: 96-107.         [ Links ]

Nwaiwu JI, Akah PA 1986. Anticonvulsant activity of the volatile oil from the fruit of Tetrapleura tatraptera. J Ethnopharmacol 18: 103-107.         [ Links ]

Occhiuto F, Limardi F, Circosta C 1995. Effects of the non-volatile residue from the essential oil of Citrus bergamia on the central nervous system. Int J Pharmacogn 33: 98-203.         [ Links ]

Oga S, Chanel D, Freitas P, Gomes Silva AC, Hanada S 1984. Pharmacological trials of crude extract of Passiflora alata. Planta Med 50: 303-306.         [ Links ]

Ojewole JAO 2000. Anticonvulsant evaluaiton of the methanolic extract of Seruridaca longipendunculata (Fresen.) (Family: Polygalaceae) root bark in mice. J Pharm Pharmacol 2: 286.         [ Links ]

Olajide OA, Awe SO, Makinde JM 1997. Pharmacological studies on Newbouldia laevis stem bark. Fitoterapia 68: 439-443.         [ Links ]

Oliveira MGM, Monteiro MG, Macaubas C, Barbosa VP, Carlini EA 1991. Pharmacologic and toxicologic effects of two Maytenus species in laboratory animals. J Ethnopharmacol 34: 29-41.         [ Links ]

Orhan I, Sener B, Choudhary MI, Khalid A 2004. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some Turkish medicinal plants. J Ethnopharmacol 91: 57-60.         [ Links ]

Ozturk Y, Aydin S, Beis R, Baser KHC, Berberoglu H 1996. Effects of Hypericum perforatum L. and Hypericum calycinum L. extracts on the central nervous system in mice. Phytomedicine 3: 139-146.         [ Links ]

Perez G, Perez L, Garcia D, Sossa M 1998. Neuropharmacological activity of Solanum nigrum fruit. J Ethnopharmacol 62: 43-48.         [ Links ]

Pei YQ, Cao LG, Xie SJ, Kai ZJ, MU QZ 1981. Central pharmacological action of Cynanchum otophyllum Schneid. Pei-Ching I Hsueh Yuan Hsueh Pao 13: 213-218.         [ Links ]

Pei YQ. 1983. Depressant action of fructus Piperis longi on the central nervous system. Chung I Tsa Chih (Engl Ed) 3: 17-22.         [ Links ]

Pereira JV, Modesto-Filho J, Agra MF, Barbosa-Filho JM 2002. Plant and plant-derived compounds employed in prevention of the osteoporosis. Acta Farm Bonaerense 21: 223-234.         [ Links ]

Pfeifer E, Zechner L 1953. About preparations of Valerian roots. Sci Pharm 21: 250.         [ Links ]

Pieretti KS, Di Giannuario A, Goleffi C, Copasso A, Nicoletti M 1993. Analgesic and anticonvulsive effects of Cadia rubra extract. Pharmacol Res 27: 41-42.         [ Links ]

Prasad S, Malholtra CL 1968. Withania ashwagandha. VI. Effect of alkaloidal fractions (actone, alcohol and water soluble) on the central nervous system. Indian J Physiol Pharmacol 12: 175-181.         [ Links ]

Putnam TJ, Merritt HH 1937. Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science 85: 525-526.         [ Links ]

Qu S, Wu Y, Wang Y, Pan D 1984. Inhibitory effect of tall oplopanax (Oplopanax elatus) oil on the central nervous system. Chung Ts'ao Yao 15: 259-261.         [ Links ]

Quintans-Júnior LJ, Almeida RN, Falcão ACGM, Agra MF, Sousa MFV, Barbosa-Filho JM. 2002. Avaliação da Atividade Anticonvulsivante de Plantas do Nordeste Brasileiro. Acta Farm Bonaer 21: 179-184.         [ Links ]

Quintans-Júnior LJ, Silva DA, Siqueira JS, Souza MFV, Barbosa-Filho JM, Almeida RN. 2007. Anticonvulsant properties of the total alkaloid fraction of Rauvolfia ligustrina Roem. et Schult. in male mice. Rev Bras Farmacogn 17: 29-34.         [ Links ]

Ramirez BED, Ruiz NN, Arellano JDQ, Madrigal BR, Michel MTV, Garzon P 1998. Anticonvulsant effects of Magnolia grandiflora l. in the rat. J Ethnopharmacol 61: 143-152.         [ Links ]

Rana SDD, Saluja AK 1990. Pharmacological screening of the alcoholic extract of the leaves of Rubus ellipticus. Indian J Pharm Sci 52: 174-177.         [ Links ]

Rauca C, Pohle W, Grunenberg K, Franze S 2000. Hypothermia inhibits pentylenetetrazol kindling and prevents kindling-induced deficit in shuttle-box avoidance. Pharmacol Biochem Behav 65: 23-30.         [ Links ]

Raza M, Shaheen F, Choudhary MI, Suria A, Atta-Ur-Rahman, Sombati S, Delorenzo RJ 2001. Anticonvulsant activities of the fs-1 subfraction isolated from roots of Delphinium denudatum. Phytother Res 15: 426-430.         [ Links ]

Reddy TN, Reddy CP, Srinivas V, Divan PV, Reddy PUM 1994. Glycogenic effect of an alkali soluble fraction from Sepia shell. Arzneimittel-Forsch 44: 1133-1135.         [ Links ]

Richens A, Perucca E 1993. Clinical pharmacology and medical treatment. In: A Textbook of Epilepsy (Eds J. Laidlaw, A. Richens and D. Chadwick). Edinburgh, Churchill Livingstone, pp. 495-560.         [ Links ]

Rocha LG, Almeida JRGS, Macedo RO, Barbosa-Filho JM 2005. A review of natural products with antileishmanial activity. Phytomedicine 12: 514-535.         [ Links ]

Rodriguez EB, Droy-Lefaix MT, Bazan NG. 1993. Decreased electroconvulsive shock-induced diacylglycerols and free fatty acid accumulation in the rat brain by Ginkgo biloba extract (EGb 761): selective effect in hippocampus as compared with cerebral cortex. J Neurochem 61: 1438-1444.         [ Links ]

Rössler AS, Schröeder H, Dodd RH, Chapouthier G, Grecksch G. 2000. Benzodiazepine receptor inverse agonist-induced kindling of rats alters learning and glutamate binding. Pharmacol Biochem Behav 67: 169-175.         [ Links ]

Rousinov KS, Athanasova-Shopova S 1966. Experimental screening of the anticonvulsive activity of certain plants used in popular medicine in Bulgaria. Acad Bulg Sci 19: 333-336.         [ Links ]

Ruiz AN, Ramirez BED, Estrada JG, Lopez PG, Garzon P 1995. Anticonvulsant activity of casimiroa edulis in comparison to phenytoin and phenobarbital. J Ethnopharmacol 45: 199-206.         [ Links ]

Said SA, El Kashef HA, El Mazar MM, Salama O 1996. Phytochemical and pharmacological studies on Lactuca sativa seed oil. Fitoterapia 67: 215-219.         [ Links ]

Sakina MR, Dandiya PC, Hamdard ME, Hameed A 1990. Preliminary psychopharmacological evaluation of Ocimum sanctum leaf extract. J Ethnopharmacol 28: 143-150.         [ Links ]

Santos FA, Rao VSN, Silveira ER 1996. Studies on the neuropharmacological effects of Psidium guyanensis and Psidium pohlianum essential oils. Phytother Res 10: 655-658.         [ Links ]

Santos FA, Rao VSN, Silveira ER 1997. The leaf essential oil of Psidium guyanensis offers protection against pentylenetetrazole-induced eizures. Planta Med 63: 133-135.         [ Links ]

Saúde-Guimarães DA, Faria AR 2007. Substâncias da natureza com atividade anti-Trypanosoma cruzi. Rev Bras Farmacogn 17: 455-465.         [ Links ]

Sayyah M, Mahboubi A, Kamalinejad M 2002. Anticonvulsant effect of the fruit essential oil of Cuminum cyminum in mice. Pharm Biol 40: 478-480.         [ Links ]

Scheuer ML, Pedley TA 1990. The evaluation and treatment of seizures. New Engl J Med 323: 1468-1474.         [ Links ]

Sharmaxvn, Barar SK, Khanna NK, Mahawar MM 1965. Some pharmacological actions of Convolvulus pluricaulis, an Indian indigenous herb. Indian J Med Res 53: 871.         [ Links ]

Shibata M, Ikoma M, Onoda M, Sato F, Sakurai N 1980. Pharmacological studies on the chinese crude drug "shoma". III. central depressant and antispasmodic actions of Cimicifuga rhizoma, Cimicifuga simplex wormsk. Yakugaku Zasshi 100: 1143-1150.         [ Links ]

Shukia B, Khanna NK, Godhwani JL 1987. Effect of brahmi rasayan on the central nervous system. J Ethnopharmacol 21: 65-74.         [ Links ]

Silva JS, Moura MD, Oliveira RAG, Diniz MFFM, Barbosa-Filho JM 2003. Natural products inhibitors of ovarian neoplasia. Phytomedicine 10: 221-232.         [ Links ]

Silva AFS, Andrade JP, Bevilaqua LRM, Souza MM, Izquierdo I, Henriques AT, Zuanazzi JAS 2006. Anxiolytic-, antidepressant- and anticonvulsant-like effects of the alkaloid montanine isolated from Hippeastrum vittatum. Pharmacol Biochem Behav 85: 148-154.         [ Links ]

Simon OR, Singh N 1986. Demonstration of anticonvulsant properties of an aqueous extract of spirit weed (Eryngium foetidum L.). W Indian Med J 35: 121-125.         [ Links ]

Smith M, Wilcox KS, White HS 2007. Discovery of antiepileptic drugs. Neurotherapeutics 4: 12-17.         [ Links ]

Singh N, Singh SP, Kohli RP, Bhargava KP 1985. Indian plants as anti-stress agents. Nat Prod Coll Pharm Univ N Carolina, Abstract-202.         [ Links ]

Sinha BN, Sasmal D, Basu SP 1997. Pharmacological studies on Melothria maderaspatana. Fitoterapia 68: 75-78.         [ Links ]

Sokomba E, Wambebe C, Chowdhury BK, Iriah J, Ogbeide ON, Orkor D 1986. Preliminary phytochemical, pharmacological and antibacterial studies of the alkaloidal extracts of the leaves of Synclisia scabrida miers. J Ethnopharmacol 18: 173-185.         [ Links ]

Souza MF, Santos FA, Rao VSN, Sidrim JJC, Matos FJA, Machedo MIL, Silveria ER 1998. Antinociceptive, anticonvulsant and antibacterial effects of the essential oil from the flower heads of Egletes viscosa L. Phytother Res 12: 28-31.         [ Links ]

Spence I, Jamieson DD, Taylor KM 1979. Anticonvulsant activity of farnesylacetone epoxide-a novel marine natural product. Experientia 35: 238.         [ Links ]

Speroni E, Minghetti A 1988. Neuropharmacologica activity of extracts from Passiflora incarnata. Planta Med 54: 488-491.         [ Links ]

Stables JP, Bertram E, Dudek FE 2003. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop. Epilepsia 44: 1472-1478.         [ Links ]

Stoyanov N, Stefanov Z, Mitrev A, Nikolova M, Vankov S, Taskov M, Peneva M 1981. Study of the contents of biologically active compounds in wild Bulgarian plants. Nauchnoizsled Khim Farm Inst 11: 90-110.         [ Links ]

Sudha S, Kumaresan S, Amit A, David J, Venkataraman BV 2002. Anti-convulsant activity of different extracts of Centella asiatica and Bacopa monnieri in animals. J Nat Rem 2: 33-41.         [ Links ]

Sugaya A, Tsuda T, Sugaya E, Takato M, Takamura K 1978. Effects of chinese medicine Saiko-Keishi-To on the abnormal bursting activity of snail neurons. Planta Med 34: 294-298.         [ Links ]

Sugaya E, Ishige A, Sekiguchi K, Iizuka S, Ito K, Sugimoto A, Aburada M, Hosoya E 1988. Inhibitory effect of TJ- 960(SK) on pentylenetetrazole-induced EEG power spectrum changes. Epilepsy Res 2: 27-31.         [ Links ]

Sugaya A, Suzuki T, Sugaya E, Yuyama N, Yasuda K, Tsuda T 1991. Inhibitory effect of Paeony root extract on pentylenetetrazol-induced eeg power spectrum changes and extracellular calcium concentration changes in rat cerebral cortex. J Ethnopharmacol 33: 159-167.         [ Links ]

Sugaya E, Sugaya A, Kajiwara K 1997. Nervous diseases and Kampo (Japanese herbal) medicine: a new paradigm of therapy against intractable nervous diseases. Brain Dev-Jpn 19: 93-103.         [ Links ]

Sun JN, Xu QP, Wu JY, Wang F, Ma LX, Chen MT, Yang CS 1991. Actions of volatile oils from the three kinds of xixin on the central nervous system. Zhongguo Yaoxue Zazhi 26: 470-472.         [ Links ]

Taesotikul T, Panthong A, Kanjanapothi D, Verpoorte R, Scheffer JJC 1998. Neuropharamcological activities of the crude alkaloidal fraction from stems of Tabernaemontana pandacaqui Poir. J Ethnopharmacol 62: 229-234.         [ Links ]

Takagi K 1977. Pharmacological studies on Ginseng. Korean Ginseng Studies. Chem Pharmacol 346-357.         [ Links ]

Tortoriello J, Lozoya X 1992. Effect of Galphimia glauca methanolic extract on neuropharmacological tests. Planta Med 58: 234-236.         [ Links ]

Tortoriello J, Ortega A 1993. Sedative effect of galphimine B, a nor-seco-triterpenoid from Galphimia glauca. Planta Med 59: 398-400.         [ Links ]

Tortoriello J, Anguilar-Santamaria L 1996. Evaluation of the calcium-antagonist, antidiarrhoeic and central nervous system activities of Baccharis serraefolia. J Ethnopharmacol 53: 157-163.         [ Links ]

Tsuda T, Kubota K, Yasuda K, Sugaya A, Sugaya E 1986. Effect of Chinese herbal medicine "Kanbaku-Taiso-To" on neuropharmacological tests. J Ethnopharmacol 15: 289-296.         [ Links ]

Tsuda T, Sugaya A, Ohguchi H, Kishida N, Sugaya E. 1997. Protective effects of peony root extract and its components on neuron damage in the hippocampus induced by the cobalt focus epilepsy model. Exp Neurol 146: 518-525.         [ Links ]

Tsuda T, Sugaya A, Kaneko E, Oghuchi H, Katoh K, Jin W, Sugaya E 1998. pharmacological studies on longgu and oyster shell. Nat Med 52: 300-309.         [ Links ]

Turski WA, Cavalheiro EA, Schwarz M, Czuczwar SJ, Kleinrok Z, Turski L 1983. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav Brain Res 9: 315-335.         [ Links ]

Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA 1989. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3: 154-171.         [ Links ]

Vasconcelos SMM, Lima NM, Sales GTM, Cunha GMA, Aguiar LMV, Silveira ER, Rodrigues ACP, Macedo DS, Fonteles MMF, Sousa FCF 2007. Anticonvulsant activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu. J Ethnopharmacol 110: 271-274.         [ Links ]

Vazquez-Freire MJ, Castro E, Lamela M, Calleja JM 1995. Neuropharmacological effects of Cystoseira usneoides extract. Phytother Res 9: 207-210.         [ Links ]

Veiga-Junior VF 2008. Estudo do consumo de plantas medicinais na Região Centro-Norte do Estado do Rio de Janeiro: aceitação pelos profissionais de saúde e modo de uso pela população. Rev Bras Farmacogn 18: 308-313.         [ Links ]

Velisek L, Kubova H, Mares P, Vachova D 1995. Kainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenotetrazol-induced seizures in the developing rats. Pharmacol Biochem Behav 51: 153-153.         [ Links ]

Vieira RA, Lapa AJ, Lima TCM 2002. Evaluation of the central activity of the ethanolic extract of Acosmium subelegans (Mohlenbr) in mice. Rev Bras Farmacogn 12: 50-51.         [ Links ]

Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC 1995. Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Med 61: 213-216.         [ Links ]

Viola H, Wasowaski C, Marder M, Wolfman C, Paladini AC 1997. Sedative and hypnotic properties of Salvia guaranitica St. Hil. and of its active principle, cirsiliol. Phytomedicine 4: 47-51.         [ Links ]

Watanabe K, Watanabe H, Goto Y, Yamaguchi M, Yamamoto N, Hagino K 1983. Pharmacological properties of magnolol and honnokiol extracted from Magnolia officinalis: central depressant effects. J Med Plant Res 49: 103-108.         [ Links ]

While HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH 2002. Discovery and preclinical development of antiepileptic drugs. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, eds. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins. p36-48.         [ Links ]

Wu C, Yu Q 1984. Pharmacological studies on Bupleurum chinense and its active ingredient, crude saikosaponin. Shenyang Yaoxueyuan Xuebao 1: 214-218.         [ Links ]

Yamahara J, Sawada T, Tani T, Nishino T, Kitagawa I, Fujimura H 1977. Biologically active principles of crude drugs. pharmacological evaluation of the crude drug "zhu". Yakugaku Zasshi 97: 873.         [ Links ]

Yen YC 1977. Antiepileptic action of traditional Chinese medicinal herbs. Chung-Hua I Hsueh Tsa Chih (Beijing) 57: 497.         [ Links ]

Yoshitomi S, Watanabe M, Kawanishi F, Satake M 2000. Quality and their sedative effects of japanese Valerian roots. Nat Med 54: 55-56.         [ Links ]

Zia A, Siddiqui BS, Begum S, Siddiqui S, Suria A. 1995. Studies on the constituents of the leaves of Nerium oleander on behavior pattern in mice. J Ethnopharmacol 49: 33-39.         [ Links ]

 

 

Received 1 October 2008
5 November 2008

 

 

* E-mail: lucindo@ufs.br

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