Antiaris toxicaria (Moraceae) was evaluated for anticonvulsant activity in rodents. Animal models used include maximal electroshock test (MEST); pentylenetetrazole-induced (PTZ) convulsions; picrotoxin-induced (PCT) convulsions; strychnine- (STR-) and 4-aminopyridine-induced convulsions. Increase in latency to seizures as well as reduction in duration and frequency of seizures indicated anticonvulsant activity. The extract was more effective in all models used except the maximal electroshock test and strychnine-induced convulsions. Antiaris toxicaria aqueous extract (200, 400, and 800？mg？kg？1) significantly ( ) shortened the duration of convulsions in PTZ- and PCT-induced seizures. Delay in the onset of convulsions in the two tests was significant ( ). Reduction in the frequency of seizures was also significant ( ) in both tests. Antiaris further delayed the onset of seizures in 4-aminopyridine model while producing 75% protection against death in mice. Diazepam (0.1, 0.3, and 1？mg？kg？1), carbamazepine (3, 10, and 30？mg？kg？1), and sodium valproate (100–400？mg？kg？1) were used as reference anticonvulsant drugs for various models. Flumazenil blocked the effect of the extract in the PTZ test significantly suggesting that Antiaris toxicaria may be acting by enhancing the effects of the GABAergic system. Antiaris toxicaria aqueous extract therefore possesses anticonvulsant activity. 1. Introduction The plant Antiaris toxicaria (family Moraceae) is an indigenous plant common in Ghanaian forests. It is known locally as “foto” or “kyenkyen” in Akan and the bark cloth tree in English [1]. Despite considerable advancements in the treatment of neurological disorders, epilepsy remains a significant therapeutic challenge [2]. Currently available antiepileptic drugs (AEDs) have debilitating adverse effects on cognition and behaviour [3]. These adverse effects are commonly and consistently observed with barbiturates, benzodiazepines, and topiramate [4, 5]. This problem is further compounded by polypharmacy which characterizes treatment of epilepsy. These problems are known to prevail more in developing countries due to lack of facilities for proper diagnosis and treatment along with monitoring of AED serum levels [6, 7]. Natural products and plants already used in traditional medicine can be a good place to start in the search for safer and more effective options. Numerous plants used for the treatment of epilepsy traditionally have been shown to be potent in models of epilepsy and several such plants remain to be scientifically validated [8]. Leonotis leonurus,
References
[1]
R. N. Mshana, Traditional Medicine and Pharmacopoeia, Contribution to the Revision of Ethnobotanical and Floristic Studies in Ghana, Science and Technology Press, CSIR, 2001.
[2]
B. A. Chindo, J. A. Anuka, L. McNeil et al., “Anticonvulsant properties of saponins from Ficus platyphylla stem bark,” Brain Research Bulletin, vol. 78, no. 6, pp. 276–282, 2009.
[3]
J. S. Duncan, “The promise of new antiepileptic drugs,” British Journal of Clinical Pharmacology, vol. 53, no. 2, pp. 123–131, 2002.
[4]
J. Vermeulen and A. P. Aldenkamp, “Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research,” Epilepsy Research, vol. 22, no. 2, pp. 65–95, 1995.
[5]
R. L. Bromley, B. A. Leeman, G. A. Baker, and K. J. Meador, “Cognitive and neurodevelopmental effects of antiepileptic drugs,” Epilepsy & Behavior, vol. 22, no. 1, pp. 9–16, 2011.
[6]
M. P. Kvalsund and G. L. Birbeck, “Epilepsy care challenges in developing countries,” Current Opinion in Neurology, vol. 25, no. 2, pp. 179–186, 2012.
[7]
J. Engel, “Epilepsy global issues for the practicing neurologist,” 2005, http://public.j.eblib.com/EBLPublic/PublicView.do?ptiID=289756.
[8]
M. Raza, F. Shaheen, M. I. Choudhary et al., “Anticonvulsant activities of ethanolic extract and aqueous fraction isolated from Delphinium denudatum,” Journal of Ethnopharmacology, vol. 78, no. 1, pp. 73–78, 2001.
[9]
E. Ngo Bum, D. L. Dawack, M. Schmutz et al., “Anticonvulsant activity of Mimosa pudica decoction,” Fitoterapia, vol. 75, no. 3-4, pp. 309–314, 2004.
[10]
P. Amoateng, E. Woode, and S. B. Kombian, “Anticonvulsant and related neuropharmacological effects of the whole plant extract of Synedrella nodiflora (L.) Gaertn (Asteraceae),” Journal of Pharmacy and Bioallied Sciences, vol. 4, no. 2, pp. 140–148, 2012.
[11]
P. K. Mante, D. W. Adongo, K. K. E. Kukuia, E. O. Ameyaw, and E. Woode, “Neuropharmacological assessment of an aqueous bark extract of Antiaris toxicaria (Pers.) Lesch. (Moraceae) in rodents,” American Journal of Pharmacology and Toxicology, vol. 7, no. 4, pp. 123–134, 2012.
[12]
NRC, Guide for the Care and Use of Laboratory Animals, The National Academies Press, 1996.
[13]
S. V. Vellucci and R. A. Webster, “Antagonism of caffeine-induced seizures in mice by Ro15-1788,” European Journal of Pharmacology, vol. 97, no. 3-4, pp. 289–293, 1984.
[14]
L. Moezi, H. Shafaroodi, A. Hojati, and A. R. Dehpour, “The interaction of melatonin and agmatine on pentylenetetrazole-induced seizure threshold in mice,” Epilepsy & Behavior, vol. 22, no. 2, pp. 200–206, 2011.
[15]
V. Paul and E. H. Subramanian, “Evidence for an involvement of nitric oxide and gamma aminobutyric acid in the anticonvulsant action of L-arginine on picrotoxin-induced convulsions in rats,” Pharmacology Biochemistry and Behavior, vol. 72, no. 3, pp. 515–519, 2002.
[16]
W. Loscher, C. P. Fassbender, and B. Nolting, “The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models,” Epilepsy Research, vol. 8, no. 2, pp. 79–94, 1991.
[17]
N. N. Bogdanov, I. I. Poletaeva, and N. V. Popova, “Pentylenetetrazol and strychnine convulsions in brain weight selected mice,” Seizure, vol. 6, no. 2, pp. 135–138, 1997.
[18]
A. Morales-Villagrán and R. Tapia, “Preferential stimulation of glutamate release by 4-aminopyridine in rat striatum in vivo,” Neurochemistry International, vol. 28, no. 1, pp. 35–40, 1996.
[19]
B. S. Meldrum, “Epilepsy and γ aminobutyric acid mediated inhibition,” International Review of Neurobiology, vol. 17, pp. 1–36, 1975.
[20]
K. Gale, “Role of GABA in the genesis of chemoconvulsant seizures,” Toxicology Letters, vol. 64-65, pp. 417–428, 1992.
[21]
G. De Sarro, G. Ferreri, P. Gareri et al., “Comparative anticonvulsant activity of some 2,3-benzodiazepine derivatives in rodents,” Pharmacology Biochemistry and Behavior, vol. 74, no. 3, pp. 595–602, 2003.
[22]
K. Gale, “GABA and epilepsy: basic concepts from preclinical research,” Epilepsia, vol. 33, supplement 5, pp. S3–S12, 1992.
[23]
B. G. Katzung, Basic and Clinical Pharmacology, McGraw-Hill, Boston, Mass, USA, 9th edition, 2004.
[24]
W. Loscher and D. Schmidt, “Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations,” Epilepsy Research, vol. 2, no. 3, pp. 145–181, 1988.
[25]
N. Upton, “Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings,” Trends in Pharmacological Sciences, vol. 15, no. 12, pp. 456–463, 1994.
[26]
M. K. Ticku and R. W. Olsen, “γ-Aminobutyric acid stimulated chloride permeability in crayfish muscle,” Biochimica et Biophysica Acta, vol. 464, no. 3, pp. 519–529, 1977.
[27]
R. W. Olsen, “The GABA postsynaptic membrane receptor-ionophore complex. Site of action of convulsant and anticonvulsant drugs,” Molecular and Cellular Biochemistry, vol. 39, pp. 261–279, 1981.
[28]
A. B. MacDermott, L. W. Role, and S. A. Siegelbaum, “Presynaptic ionotropic receptors and the control of transmitter release,” Annual Review of Neuroscience, vol. 22, pp. 443–485, 1999.
[29]
G. M. Khan, I. Smolders, G. Ebinger, and Y. Michotte, “Flumazenil prevents diazepam-elicited anticonvulsant action and concomitant attenuation of glutamate overflow,” European Journal of Pharmacology, vol. 407, no. 1-2, pp. 139–144, 2000.
[30]
K. H. Backus, P. Pflimlin, and G. Trube, “Action of diazepam on the voltage-dependent Na+ current. Comparison with the effects of phenytoin, carbamazepine, lidocaine and flumazenil,” Brain Research, vol. 548, no. 1-2, pp. 41–49, 1991.
[31]
Y. Ishizawa, K. Furuya, S. Yamagishi, and S. Dohi, “Non-GABAergic effects of midazolam, diazepam and flumazenil on voltage-dependent ion currents in NG108-15 cells,” NeuroReport, vol. 8, no. 11, pp. 2635–2638, 1997.
[32]
A. Rostock, C. Tober, C. Rundfeldt et al., “D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures,” Epilepsy Research, vol. 23, no. 3, pp. 211–223, 1996.
[33]
C. Rundfeldt, “The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells,” European Journal of Pharmacology, vol. 336, no. 2-3, pp. 243–249, 1997.
[34]
B. Hecht, “Retigabine. A novel anticonvulsant drug for the adjunctive treatment of partial seizures,” Medizinische Monatsschrift fur Pharmazeuten, vol. 35, no. 5, pp. 166–171, 2012.
[35]
P.-S. Hu, C. Benishin, and B. B. Fredholm, “Comparison of the effects of four dendrotoxin peptides, 4-aminopyridine and tetraethylammonium on the electrically evoked [3H]noradrenaline release from rat hippocampus,” European Journal of Pharmacology, vol. 209, no. 1-2, pp. 87–93, 1991.
[36]
P.-S. Hu and B. B. Fredholm, “4-Aminopyridine-induced increase in basal and stimulation-evoked [3H]-NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control,” British Journal of Pharmacology, vol. 102, no. 3, pp. 764–768, 1991.
[37]
P.-S. Hu, S. Jin, and B. B. Fredholm, “4-Aminopyridine-induced noradrenaline release from the rat hippocampus depends on the activation of glutamate receptors of the non-NMDA type,” Acta Physiologica Scandinavica, vol. 143, no. 1, pp. 139–140, 1991.
[38]
R. Tapia, L. Medina-Ceja, and F. Pe？a, “On the relationship between extracellular glutamate, hyperexcitation and neurodegeneration, in vivo,” Neurochemistry International, vol. 34, no. 1, pp. 23–31, 1999.
[39]
H. Lundh, “Effects of 4-aminopyridine on neuromuscular transmission,” Brain Research, vol. 153, no. 2, pp. 307–318, 1978.
[40]
B. S. Meldrum, “Excitatory amino acid receptors and disease,” Current Opinion in Neurology and Neurosurgery, vol. 5, no. 4, pp. 508–513, 1992.
[41]
R. L. Macdonald and M. Kevin Kelly, “Antiepileptic drug mechanisms of action,” Epilepsia, vol. 36, supplement 2, pp. S2–S12, 1995.
[42]
E. D. Bigler, “Comparison of effects of bicuculline, strychnine, and picrotoxin with those of pentylenetetrazol on photically evoked afterdischarges,” Epilepsia, vol. 18, no. 4, pp. 465–470, 1977.
