Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (α-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson's disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate's mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.

The central nervous system (CNS) presents both challenges and opportunities to researchers of redox biochemistry. The CNS is sensitive to oxidative damage during aging or disease; excellent transgenic models of specific neurodegenerative diseases have been created that reproduce oxidative stress components of the corresponding human disorder. Mouse models of familial amyotrophic lateral sclerosis (ALS) based on overexpressed mutant human Cu, Zn-superoxide dismutase (SOD1) are cases in point. These animals experience predictably staged, age-dependent motor neuron degeneration with profound cellular and biochemical damage to nerve fibers and spinal cord tissue. Severe protein and lipid oxidation occurs in these animals, apparently as an indirect consequence of protein aggregation or cytopathic protein-protein interactions, as opposed to aberrant redox catalysis by the mutant enzyme. Recent studies of G93A-SOD1 mice and rats suggest that oxidative damage is part of an unmitigated neuroinflammatory reaction, possibly arising in combination from mitochondrial dysfunction plus pathophysiologic activation of both astrocytes and microglia. Lesions to redox signal-transduction pathways in mutant SOD1+ glial cells may stimulate broad-spectrum upregulation of proinflammatory genes, including arachidonic acid-metabolizing enzymes [e.g., cyclooxygenase-II (COX-II) and 5-lipoxygenase (5LOX)]; nitric oxide synthase (NOS) isoforms; cytokines (particularly tumor necrosis factor alpha, TNF-alpha); chemokines; and immunoglobulin Fc receptors (FcgammaRs). The integration of these processes creates a paracrine milieu inconsistent with healthy neural function. This review summarizes what has been learned to date from studies of mutant SOD1 transgenic animals and demonstrates that the G93A-SOD1 mouse in particular is a robust laboratory for the study of neuroinflammation and redox biochemistry.

Chronic administration of ethanol results in the development of tolerance and dependence. The molecular mechanism underlying these behavioral actions of ethanol is poorly understood. Several lines of evidence have suggested that some of the pharmacological actions of ethanol are mediated via a potentiation of GABAergic transmission. Chronic ethanol administration results in a reduction in the GABAA receptor-mediated 36Cl- uptake in cortical synaptoneurosomes and primary cultured neurons. We and others have shown that it also results in a 40-50% reduction in GABAA receptor alpha-subunit mRNA levels in the rat cerebral cortex. In the present study, we investigated the expression of alpha 1, alpha 2, and alpha 3 subunits of the GABAA receptor in the cerebral cortex and the alpha 1 subunit in the cerebellum by immunoblotting using polyclonal antibodies raised against alpha 1-, alpha 2-, and alpha 3-subunit polypeptides following chronic ethanol treatment. These results reveal that chronic ethanol administration to rats results in a 61 +/- 4% reduction in level of the GABAA receptor alpha 1 subunit (51 kDa), 47 +/- 8% reduction in level of the alpha 2 subunit (53 kDa), and 30 +/- 7% reduction in level of the alpha 3 subunit (59 kDa) in the cerebral cortex and a 56 +/- 5% reduction in content of the alpha 1 subunit in the cerebellum. In summary, this ethanol-induced reduction in content of the GABAA receptor alpha subunits may underlie alterations in the GABAA receptor function and could be related to cellular adaptation to the functional disturbance caused by ethanol.

Many neurological diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), are now recognized to share atypical inflammatory reactions as a major pathological feature. Neuroinflammation can both be a cause, and a consequence, of chronic oxidative stress. Cytokine-stimulated microglia generate copious amounts of reactive oxygen and reactive nitrogen species, creating a stress upon ambient neurons. Conversely, oxidants can stimulate pro-inflammatory gene transcription in glia, leading to various inflammatory reactions. This review compares literature regarding neuroinflammation in AD and ALS, with special emphasis on roles played by tumor necrosis factor alpha (TNFα) and aberrant arachidonic acid metabolism in the genesis of chronic oxidative conditions. Based on our observations made in the G93A-SOD1 mouse model of ALS, and a body of Alzheimer's disease findings, we hypothesize a prominent pathological role for the TNFα-signaling axis and neuroinflammation in the pathogenesis of both diseases. A discussion is made regarding the relevance of neuroinflammation to potential therapeutic implications for both ALS and AD.