Ginsenosides attenuate kainic acid-induced synaptosomal oxidative stress via stimulation of adenosine A(2A) receptors in rat hippocampus.

Treatment with ginsenosides attenuated KA-induced seizures and oxidative stress in the synaptosome, and reduced synaptic vesicles at the presynaptic terminals dose-dependently. The adenosine A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl) xanthine reversed the ginsenoside-mediated pharmacological actions. Neither the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine nor the adenosine A(2B) receptor antagonist alloxazine affected the ginsenoside-mediated pharmacological actions. Our results suggest that ginsenosides block KA-induced synaptosomal oxidative stress, associated with hippocampal degeneration, through activation of adenosine A(2A) receptors.

Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice.

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.

Role of glutathione peroxidase in the ontogeny of hippocampal oxidative stress and kainate seizure sensitivity in the genetically epilepsy-prone rats.

Oxidative stress may contribute to epileptogenicity in genetic models of epilepsy. To address this, we examined the enzymatic activity of cytosolic Cu/Zn superoxide dismutase (SOD-1), mitochondrial Mn superoxide dismutase (SOD-2), and glutathione peroxidase (GPx) in the developing hippocampus of genetically epilepsy-prone rats (GEPR-9s). We also measured changes in the GSH/GSSG ratio, lipid peroxidation, and protein oxidation at post-natal days (PD) 7, 30, and 90, respectively. Compared with control Sprague-Dawley (SD) rats, GEPR-9s showed similar SOD-1 and SOD-2 activity but lower GPx activity. Epilepsy-prone rats also showed lower GSH/GSSG ratios than controls, and more lipid peroxidation (as measured by malondialdehyde levels) and protein oxidation (as measured by carbonyl levels). Treatment with kainic acid (KA) resulted in more pronounced seizures, less GPx activity, and lower GSH/GSSG ratios in GEPR-9s than in controls, but KA did not significantly affect SOD-1 or SOD-2 activity, suggesting that GEPR-9s do not compensate for reduced GPx activity by increasing SOD. Moreover, KA treatment resulted in significantly a lower GSH/GSSG ratio and GPx-like immunoreactivity and higher malondialdehyde and carbonyl levels in GEPR-9s than in controls. These findings were more evident in GEPR-9s at PD 90 than at PD 30, indicating that oxidative stress is age-dependent. Double-labeling immunocytochemical analysis demonstrated co-localization of GPx-immunoreactive glia-like cells and reactive astrocytes, as labeled by glial fibrillary acidic protein (GFAP). This suggests that mobilization of astroglial cells for synthesis of GPx protein is a response to KA insult, intended to decrease the neurotoxicity induced by peroxides. These responses were more pronounced in control SD rats than in GEPR-9s. Our results suggest that impairment of the GPx (including glutathione)-mediated antioxidant system contributed to epileptogenesis in GEPR-9s.

Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats.

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.