Dopamine (DA)-or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to beinvolved not only in adverse reactions induced by longterm L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA-or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-α-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The

Recently, it has been reported that in¯ammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non-steroidal anti-in¯ammatory drugs reduce the risk for Alzheimer's disease. In the present study, we examined nitric oxide radical quenching activity of non-steroidal anti-in¯ammatory drugs and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non-steroidal anti-in¯ammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dosedependently scavenged generated nitric oxide radicals. In experiments of nitric oxide radical donor, NOC18-induced neuronal damage, these four non-steroidal drugs signi®cantly prevented the NOC18-induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase-like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro, showed almost no protective effects against NOC18-induced cell toxicity. These results suggest that the protective effects of the former four non-steroidal anti-in¯ammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO´quenching activities represent novel effects of nonsteroidal anti-in¯ammatory drugs. Our ®ndings identi®ed novel pharmacological mechanisms of these drugs to exert not only their anti-in¯ammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.

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Abstract:We examined the effects of oxidative stress on rat cultured mesencephalic neurons and glial cells. Glial cells were more resistant to 6-hydroxydopamine (6-OHDA) and H 2 O 2 toxicity than neurons. In glial cells, incubation with 6-OHDA and H 2 O 2 induced a significant increase in the expression of ␥-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which correlated well with increased TPA-response element (TRE)-binding activity. Furthermore, a subsequent elevation in cellular total glutathione content was also observed. In neurons, both agents decreased TRE-binding activity, and these cells failed to up-regulate the glutathione synthesis. We also examined the mechanisms of the neuroprotective effects of glial cells using a glia conditioned medium. Neurons maintained in glia conditioned medium up-regulated the level of TRE-binding activity, ␥-glutamylcysteine synthetase mRNA expression, and total glutathione content in response to 6-OHDA or H 2 O 2 , and became more resistant to both agents than cells maintained in a normal medium. Neurons maintained in normal medium failed to up-regulate the glutathione synthesis. Our results suggest that transcriptional up-regulation of glutathione synthesis in glial cell appears to mediate brain glial cell resistance against oxidative stress, and that glial cells protect neurons via transcriptional up-regulation of the antioxidant system.

These results provide new pharmacological evidence for the effects of ZNS. ZNS markedly increased GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation via S100beta production or secretion. ZNS acts as a neuroprotectant against oxidative stress and progressive dopaminergic neurodegeneration.