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Published on: March 23, 2011
Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice
Eun-Joo Shin1, Ji Hoon Jeong, Guoying Bing
1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
Abstract:
We have demonstrated that kainate (KA) induces a reduction in mitochondrial Mn-superoxide dismutase (Mn-SOD) expression in the rat hippocampus and that KA-induced oxidative damage is more prominent in senile-prone (SAM-P8) than senile-resistant (SAM-R1) mice. To extend this, we examined whether KA seizure sensitivity contributed to mitochondrial degeneration in these mouse strains. KA-induced seizure susceptibility in SAM-P8 mice paralleled prominent increases in lipid peroxidation and protein oxidation and was accompanied by significant impairment in glutathione homeostasis in the hippocampus. These findings were more pronounced in the mitochondrial fraction than in the hippocampal homogenate. Consistently, KA-induced decreases in Mn-SOD protein expression, mitochondrial transmembrane potential, and uncoupling protein (UCP)-2 expression were more prominent in SAM-P8 than SAM-R1 mice. Marked release of cytochrome c from mitochondria into the cytosol and a higher level of caspase-3 cleavage were observed in KA-treated SAM-P8 mice. Additionally, electron microscopic evaluation indicated that KA-induced increases in mitochondrial damage and lipofuscin-like substances were more pronounced in SAM-P8 than SAM-R1 animals. These results suggest that KA-mediated mitochondrial oxidative stress contributed to hippocampal degeneration in the senile-prone mouse.
Insights
Kainate (KA) causes oxidative stress and mitochondrial damage in the hippocampus, particularly in senile-prone mice. This neurodegeneration highlights KA
Area of Science:
- Neuroscience
- Oxidative Stress Research
- Mitochondrial Biology
Background:
- Kainate (KA) administration is known to induce oxidative damage in the hippocampus.
- Senescence-prone (SAM-P8) mice exhibit greater susceptibility to KA-induced oxidative damage compared to senescence-resistant (SAM-R1) mice.
Purpose of the Study:
- To investigate the role of KA-induced seizure susceptibility in mitochondrial degeneration.
- To compare mitochondrial dysfunction and oxidative stress markers in SAM-P8 and SAM-R1 mice following KA administration.
Main Methods:
- Kainate administration to SAM-P8 and SAM-R1 mice.
- Assessment of lipid peroxidation, protein oxidation, and glutathione homeostasis in hippocampal homogenates and mitochondrial fractions.
- Measurement of Mn-superoxide dismutase (Mn-SOD) protein expression, mitochondrial transmembrane potential, and uncoupling protein (UCP)-2 expression.
- Analysis of cytochrome c release, caspase-3 cleavage, and mitochondrial morphology via electron microscopy.
Main Results:
- KA-induced seizures in SAM-P8 mice correlated with increased lipid peroxidation, protein oxidation, and impaired glutathione homeostasis.
- Mitochondrial fractions showed more pronounced oxidative damage than hippocampal homogenates.
- SAM-P8 mice exhibited greater KA-induced decreases in Mn-SOD, mitochondrial transmembrane potential, and UCP-2 expression.
- KA treatment led to increased cytochrome c release and caspase-3 cleavage in SAM-P8 mice, alongside more significant mitochondrial damage and lipofuscin accumulation.
Conclusions:
- KA-mediated mitochondrial oxidative stress significantly contributes to hippocampal degeneration in senile-prone mice.
- Mitochondrial dysfunction is a key factor in the heightened vulnerability of SAM-P8 mice to KA-induced neurotoxicity.
