A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetically epilepsy-prone rats, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.

Tumor necrosis factor-␣ (TNF-␣

Ginsenoside Re, one of the main constituents of Panax ginseng, possesses novel antioxidant and anti-inflammatory properties. However, the pharmacological mechanism of ginsenoside Re in dopaminergic degeneration remains elusive. We suggested that protein kinase C (PKC) δ mediates methamphetamine (MA)-induced dopaminergic toxicity. Treatment with ginsenoside Re significantly attenuated methamphetamine-induced dopaminergic degeneration in vivo by inhibiting impaired enzymatic antioxidant systems, mitochondrial oxidative stress, mitochondrial translocation of protein kinase Cδ, mitochondrial dysfunction, pro-inflammatory microglial activation, and apoptosis. These protective effects were comparable to those observed with genetic inhibition of PKCδ in PKCδ knockout (-/-) mice and with PKCδ antisense oligonucleotides, and ginsenoside Re did not provide any additional protective effects in the presence of PKCδ inhibition. Our results suggest that PKCδ is a critical target for ginsenoside Re-mediated protective activity in response to dopaminergic degeneration induced by MA.

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