EPILEPTIFORM EXCITABILITY IN MICE HIPPOCAMPUS IS TRIGGERED BY LIPID PEROXIDATION (LPO) ACTIVATION AND DEPENDS ON THE CU/ZN-SUPEROXIDE DISMUTASE (SOD1) LEVEL

A.R. Koudinov^1,2 , N.V. Koudinova²

1. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation

2. Weizmann Institute of Science, Department of Neurobiology and Biological Regulation, Rehovot 76100, Israel
 

It is known for two decades [1] that epileptic activity in rodents and in patients with various forms of epilepsy [2] is accompanied and may be inhibited by LPO activation and inhibition, respectively. The administration of antioxidants prevents the effect of LPO activation and is beneficial in patients and in lab animals, sharply lowering chemically (ex. kainic acid-, bemegride-, penicillin-, iron salts-, hyperbaric oxygen-) and physically (ex. electrically) induced epileptic activity. However, it is still unknown whether enhanced LPO is a consequence or a cause of the epileptiform discharges. To elucidate this pivotal question we studied the effect of 2,2’-azobis (2-amidinopropane) dihydrochloride (AAPH), an LPO inducer, on electrical properties of mice ex-vivo hippocampal slices, and their modulation by vitamin E, an LPO blocker. We extracellularly recorded evoked field potentials and measured LPO levels by the formation of malondialdehyde, an LPO product, in a thiobarbituric acid test. The analysis was performed as we described [3], except that the electrodes were positioned in the pyramidal cell layer of the hippocampal CA1 area to record field population spikes (fPS). We studied wild type (WT) and transgenic mice (TG), genetically modified to overexpress human SOD1 [4]. TG (versus WT) slices possessed increased LPO levels, mimickng the LPO profile in normal state versus patients with epilepsy (having 20-25% decrease in the SOD activity [5]), respectively. Preincubation of slices with AAPH (1mM) caused reversible (i.e. AAPH washout dependent) increase in fPS amplitude and number (bursting) in response to single stimuli in both WT and TG. The effect was stronger in WT slices, although not statistically different from the SOD1 TG slices. In addition, at high stimulus intensity the increase in amplitude of the second and third PS was lower in the TG. Vitamin E reduced the epileptiform effect of AAPH; this reversal required lower dose of Vitamin E in the TG compared to WT. Our data imply i) LPO activation as an epileptogenesis cause, and ii) the role of SOD in buffering epileptic vulnerability. This knowledge may represent a fundamental for understanding the mechanism of the epilepsy.

References:

[1] Zh Nevropatol Psikhiat Korsakova 1981;81(6):812-5.
[2] ibid 1984;84(6):892-7.
[3] J Neurosci 1999;19:9412-25.
[4] Neurosci Lett 1998;51:S23.
[5] Biull Eksp Biol Med 1993;116(10):362-4.

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