Oxidative stress is involved in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and HIV neuroAIDS. In this study, we have investigated an agent, phenylbutyric acid, that ameliorates cell death in murine astrocytes infected with ts1 MoMuLV (ts1). Phenylbutyric acid, an aromatic short chain fatty acid, was shown to prevent the loss of catalase that occurs in ts1 infected astrocytes, and to prevent ts1-mediated cell death. Cell cotransfection studies demonstrated that phenylbutyric acid activates peroxisome proliferator receptors (PPARs) in astrocytes, and binds to the peroxisome proliferator-activated receptors alpha and gamma. This observation suggests that the effects of PBA may be mediated by PPARs in astrocytes. Phenylbutyric acid also maintained catalase protein levels in brain of ts1-infected mice, and delayed the hindlimb paralysis caused by ts1 infection. Because PBA activates peroxisome proliferator-activated receptors and prevents loss of catalase, we suggest that ts1-induced oxidative stress in infected astrocytes that is alleviated by PBA is mediated via PPARalpha and/or PPARgamma.