Sulindac for stroke treatment: neuroprotective mechanism and therapy.

Abstract

Sulindac, a widely used nonsteroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced by methionine sulfoxide reductase to its active form as an inhibitor of cyclooxygenase 1 and 2. The drug has been shown to elicit tissue protection by processes that may include at least three functions: antioxidant, preconditioning and anti-inflammatory. Sulindac demonstrates neuroprotection that involves inhibition of mitochondrial calcium overload or a decrease in protein oxidation. We have demonstrated the induction by sulindac treatment of pro-survival proteins Hsp27, Akt and Bcl-2 in the ischemic penumbra and core of the central nervous system (CNS) infarct in a rat model of ischemic stroke. Our findings point to sulindac acting on the endoplasmic reticulum (ER) to decrease ATF-6 and on the mitochondrion to increase Bcl-2 as well as decrease pro-apoptotic components BAK and PUMA. The resulting decrease in ER stress and reduction in apoptosis underlies the protective effect of sulindac in reducing infarct size following transient focal brain ischemia. The potent neuroprotective effect of sulindac in the stroke model is obtained with low-dose administration of the drug pointing to the potential of sulindac as a valuable neuroprotective agent against oxidative stress in cerebral ischemia.