12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

The enzyme 12/15-lipoxygenase (LOX) oxidizes various free fatty acids, including arachidonic acid (AA). In the brain, the principal 12/15-LOX metabolites of AA are 12(S)-HETE and 15(S)-HETE. PPAR gamma is a nuclear receptor whose activation is neuroprotective through its anti-inflammatory properties. In this study, we investigate the involvement of 12(S)-and 15(S)-HETE in the regulation of PPAR gamma following cerebral ischemia and their effects on ischemia-induced inflammatory response. We show here the increased expression of 12/15-LOX, predominantly in neurons, and elevated production of 12(S)-HETE and 15(S)-HETE in ischemic brain. The exogenous 12(S)-and 15(S)-HETE increase PPAR gamma protein level, nuclear translocation, and DNA-binding activity in ischemic rats, suggesting the activation of PPAR gamma. This effect was further confirmed by showing the increased PPAR gamma transcriptional activity in primary cortical neurons when incubated with 12(S)- or 15(S)-HETE. Moreover, both 12(S)-and 15(S)-HETE potently inhibited the induction of nuclear factor-kappa B, inducible NO synthase, and cyclooxygenase-2 in ischemic rats, and elicited neuroprotection. The reversal of the effects of 12(S)-and 15(S)-HETE on pro-inflammatory factors by PPAR gamma antagonist GW9662 indicated their actions were mediated via PPAR gamma. Thus, the induction of 12(S)and 15(S)-HETE during brain ischemia suggests that endogenous signals of neuroprotection may be generated.