Kindling, seizures

If a subconvulsive stimulus is applied, generally in rats, at regular intervals, e.g. daily for some two weeks to a specific brain area, especially the amygdala or hippocampus, then eventually full localised (partial) or secondary generalised seizures develop. A similar effect can be obtained by the repeated localised injection of subconvulsive doses of some convulsants. The ability of a drug to reduce the kindled seizure itself may be indicative of value in partial seizure but if it slows the actual development of kindling that may indicate some ability to retard epileptogenesis. 

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

We have evaluated the dose-related effects of PCP, ketamine, and selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of drugs because of the slow rate of acquisition of the fully kindled seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure in the same rats. 

The rats were next administered twice daily hippocampal stimulation (2xthreshold) until three consecutive stage V convulsive responses (Racine 1972) were obtained, indicating that the rats were fully kindled. The average number of stimulations to achieve the kindled state was 41.4 2.3 stimulations. Drug effects on seizure threshold and the kindled seizure were assessed as described above for the prekindled seizure. 

TABLE 1. Effect of PCP, ketamine and selected anticonvulsants on the duration and severity of hippocampal kindled seizures... 

During the acquisition of kindled seizures, a progressive recruitment of structures into a network of neuronal circuits capable of supporting seizures has been described (Engel et al. 1978). 

Bowyer, J.F., and Albertson, T.E. The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures. Neuropharmacoloav 21 985-990, 1982. 

Bowyer, J.F. Albertson, T.E. and Winters, W.W. Cortical kindled seizures Modification by excitant and depressant drugs. 

Freeman, F.G. Jarvis, M.F. and Duncan, P.M. Phencyclidine raises kindled seizure thresholds. Pharmacol Biochem Behav 16 1009-1011, 1982. 

Mechanism of tolerance. The molecular events involved in the development of tolerance to carbamazepine have not been clearly identified. However, in a preclinical animal model using amygdala-kindled seizures, S. R. B. Weiss and colleagues (1995) in our laboratory have found that the variety of seizure-induced adaptive changes that usually emerge following seizures fail to do so with development of tolerance to the anticonvulsant effects of carbamazepine. The loss of these adaptive changes, such as increases in... 

Mucha RF, Pineal JPJ Post seizure inhibition of kindled seizures. Exp Neurol 18 1-13, 1968... 

Post RM, Weiss SRB A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures. Mol Neurobiol... 

Weiss SRB, Post RM, Sohn E, et al Cross tolerance between carbamazepine and valproate on amygdala-kindled seizures. Epilepsy Res 16 37-44, 1993 Weiss SRB, Clark M, Rosen JB, et al Contingent tolerance to the anticonvulsant effects of carbamazepine relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 20 305-325, 1995 Weissman MM Panic disorder impact on the quality of life. J Clin Psychiatry 52 [suppl) 6-8, 1991... 

It is an inhibitor of GABA transaminase which degrades GABA. It suppresses maximal electroshock and kindled seizures and is used in partial seizure with or without generalization. 

Volk, H.A., Potschka, H., and Loscher, W. (2004) Increased expression of the multidrug transporter P-glycoprotein in limbic brain regions after amygdala-kindled seizures in rats. Epilepsy Research, 58 (1), 67-79. 

Hori A, Tandon P, Holmes GE, Stafstrom CE. Ketogenic diet effects on expression of kindled seizures and behavior in adult rats. Epilepsia 1997 38 750-758. 

Mathem G, Bertram E, Babb T, Pretorius J, Kuhlman P, Spradlin S, et al. In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic stains model correlates with greater aberrant fascia dentata excitatory and inhibitory axon sprouting, and increased staining forN-methyl-D aspartate, AMPA and GABA-A receptors. Neuroscience 1997 77 1003-1019. 

Static, transient and permanent organization of GABA receptor expression in cal-bindin-positdve interneurons in response to amygdala kindled seizures. J Neurochem 91 144-154... 

Spontaneous audiogenic, and amygdaloid kindled seizure activity. Toxicol Appl Pharmacol 92 436-444. 

Weiss, S.B.R., Li, X.L., Rosen, J.B., Li, H., and Heynen, T. Post RM. Quenching inhibition of development and expression of amygdale kindled seizures with low frequency stimulation. Neuroreport 1995,4 2171. 

Hori, A., Tandon, R, Holmes, G.L. Stafstrom, C.E. (1997) Epilepsia, 3 750-758. Ketogenic diet Effects on expression of kindled seizures and behavior of adult rats. 

Neurogenesis has been demonstrated in rodents, triggered by stimuli such as brief seizures. Secondarily generalized kindled seizures result in two- to threefold... 

Glial cell activation and proliferation with upregulation of glial-fibrillary acidic protein is seen with kindled seizures in the hippocampus. This phenomenon is time-dependent and even reversible (Torre et al., 1993 Adams et al, 1998). 

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