Hippocampal Injury from Free Radical Induced Seizures: Effect of Collapse of Glutamate Regulation.
Abstract number :
2.078
Submission category :
Year :
2001
Submission ID :
249
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
Y. Ueda, Dr, Psychiatry, Miyazaki Medical College, Miyazaki, Japan; T. Doi, Dr, Psychiatry, Miyazaki Medical College, Miyazaki, Japan; Y. Hayashi, Dr, Psychiatry, Miyazaki Medical College, Miyazaki, Japan; A. Nakajima, PhD, Chemistry, Miyazaki Medical Col
RATIONALE: Mesial temporal sclerosis is associated with seizures but specific pathogenesis is unknown. Since neuronal membranes within limbic structures may be vulnerable to free radical induced lipid peroxidation, we studied mechanisms of hippocampal vulnerability by monitoring changes in extracellular nitroxide radicals, glutamate, EEG, and histopathology. Blood barin barrier (BBB)-permeable nitroxide radical, methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy(PCAM), has recently been developed, which makes it possible to investigate the direct reactivity of free radical against the neuronal membrane in the brain. We used in this study PCAM to discuss the mechanism of hippocampal vulnerability.
METHODS: Both treated and control Wistar rats underwent stereotaxic placement of a microdialysis probe and electrodes into neocortex or ventral hippocampus. Five days later rats were given PCAM in saline (64umol/kg; 8ml in saline/kg, i.p.). Sequential changes in extracellular nitroxide radicals were measured with electron paramagnetism resonance (EPR) spectroscopy, and extracellular glutamate levels with microdialysis to an on-line enzyme fluorometer.
RESULTS: Acute seizures were induced by PCAM injection, with epileptiform discharges in hippocampus and cortex. Nitroxide radicals reached maximum 6-8min after PCAM, followed by decrement. Cortical and hippocampal extracellular glutamate were increased 15-20 min. Cortical glutamate declined while hippocampal extracellular glutamate levels remained increased. By twenty-four hrs after PCAM injection, cortical extracellular glutamate and antioxidants efficacy equaled control but pyramidal cell loss was found only in hippocampal CA1.
CONCLUSIONS: PCAM caused seizures associated with failure of free radical quenching. Glutamate was increased acutely in cortex but was sustained in hippocampus. Sustained increased in extracellular glutamate and decreased antioxidant quenching in the hippocampus resulted in the hippocampal neuronal injury. Failure to observe histopathological changes in cortical regions suggests that glutamate increase combined with increased free radicals is required for neuronal injury induced by seizures.
Support: This study was partially supported by a Grant-in-Aid for Encouragement of Young Scientists (12770537) from the Ministry of Education, Science, Sport and Culture, Japan. (to Y.U.)