Epilepsy models

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

Schwartzkroin, P. A. Epilepsy Models, mechanisms and concepts. Cambridge Cambridge University Press, 1993. 

Buhl, E. H., Otis, T. S. and Mody, I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 271 369-373,1996. 

Yegin A., Akbas S. H., Ozben T., and Korgun D. K. (2002). Secretory phospholipase A2 and phospholipids in neural membranes in an experimental epilepsy model. Acta Neurol. Scand. 106 258-262. 

Several NMDA receptor antagonists have been synthesized and tested in stroke models, epilepsy models, and in clinical trials. Many of the antagonists are limited by side effects such as hemodynamic abnormalities, hypotension, neuronal vacuolation, memory disturbances, cognitive disturbances, motor dysfunction, seizures, hallucinations, unpleasant dreams, psychotomimetic episodes, and other effects. This has made the search difficult for NMDA receptor antagonists that can be used as neu-roprotective agents. 

Yehuda and co-workers were the first to demonstrate that PUFAs can have an anticonvulsant effect in vivo (Yehuda, Carasso Mostofsky, 1994). They administered a mixture of a-linolenic/linoleic acid in a ratio of 1 4 to rats for 3 wk and assessed the protection against acute convulsant doses of pentylenetetrazole (PTZ), repeated subconvulsive doses of PTZ (chemical kindling), in rats made epileptic by a TeCI, injection in the amygdala and in rats made seizure-prone to acoustic stimulation by repeated injection with p-cresol. In all epilepsy models, the treatment either prevented the occurrence of seizures or increased the threshold for convulsions and diminished the severity and duration. 

In conclusion, in vitro studies on hippocampal neurons and in vivo studies in experimental epilepsy models have shown that PUFAs, especially DHA, in principle can have an anticonvulsant action. At low-micro molar concentrations, they exhibit the same effects as well-known antiepileptic drugs like carbamazepine, phenytoin, and valproic acid, in that they reduce sodium currents by shifting the voltage dependence of the inactivation in the hyperpolarizing direction and delaying the recovery of inactivation, without effect on activation. The manner in which the sodium current is reduced should increase the threshold for action potential generation and limit the firing rate, which has, indeed, been shown recently for CAl and CA3 hippocampal neurons (Xiao Li, 1999). The selective... 

Pitkanen A. Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models. Epilepsy Res 2002 50 141-160. 

Treatment during or after brain injury in chronic epilepsy models, such as SE and kindling, reduce cell loss and neuronal death. Such neuroprotection could contribute to modification of or delay in the development of epilepsy. 

McNamara, JO, Bonhaus, W, Shin, C. The kindling model of epdepsy In Schwartzkroin PA, editor. Epilepsy models, mechanisms, and concepts. Cambridge Cambridge University Press, 1993 21 7... 

Interest is growing in the role of glial cells in epilepsy (Binder and Steinhauser, 2006). Direct stimulation of astrocytes causes neuronal synchronization in acute epilepsy models (Tian et al., 2005). Like neurons, astrocytes exhibit calcium-induced release of glutamate which provides excitation to neurons in the vicinity (Volterra and Meldolesi, 2005). Glial cells show plasticity with stractural alterations in receptors, membrane channels, and transporters in both experimental epilepsy and human tissue. 

Gonzalez-Sulser A, Wang J, Motamedi GK, Avoh M, Vicini S, Dzakpasu R (2011) The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi-electrode array. Neuropharmacology 60 1142-1153. 

Andersen, P., Gjerstad, L., and Langmoen, 1. A., 1978ft, A cortical epilepsy model in vitro, in Abnormal Neuronal Discharges (N. Chalazonitis and M. Boisson, eds.). Raven Press, New York. 

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