Activation of peroxisome proliferator-activated receptor-γ by a 12/15-lipoxygenase product of arachidonic acid: a possible neuroprotective effect in the brain after experimental intracerebral hemorrhage

OBJECTIVE In this study, the authors investigated the involvement of 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in the regulation of peroxisome proliferator-activated receptor-gamma (PPAR gamma) after intracerebral hemorrhage (ICH) and its effects on hemorrhage-induced inflammatory response and oxidative stress in an experimental rodent model. METHODS To simulate ICH in a rat model, the authors injected autologous whole blood into the right striatum of male Sprague-Dawley rats. The distribution and expression of 12/15-lipoxygenase (12/15-LOX) were determined by immunohistochemistry and Western blot analysis, respectively. Immunofluorescent double labeling was used to study the cellular localization of 12/15-LOX, and 15(S)-HETE was measured with a 15(S)-HETE enzyme immunoassay kit. Neurological deficits in the animals were assessed through behavioral testing, and apoptotic cell death was determined with terminal deoxynucleotidyl transferase mediated biotinylated dUTP nick-end labeling. RESULTS Rats with ICH had increased expression of 12/15-LOX predominantly in neurons and also in oligodendrocytes, astrocytes, and microglia. Moreover, ICH elevated production of 15(S)-HETE in the brain area ipsilateral to the blood injection. The PPAR gamma agonist, exogenous 15(S)-HETE, significantly increased PPAR gamma protein levels and increased PPAR gamma-regulated gene (i.e., catalase) expression in the ICH rats. Reduced expression of the gene for the proinflammatory protein nuclear factor-kappa B coincided with decreased neuron damage and improved functional recovery from ICH. A PPAR gamma antagonist, GW9662, reversed the effects of exogenous 15(S)-HETE on the PPAR gamma-regulated genes. CONCLUSIONS The induction of 15(S)-HETE during simulated ICH suggests generation of endogenous signals of neuroprotection. The effects of exogenous 15(S)-HETE on brain hemorrhage induced inflammatory responses and oxidative stress might be mediated via PPAR gamma.