PPARδ may also promote cell survival after ischemic insults. In particular, GW501516 significantly reduced cerebral vascular endothelial cell degeneration in an OGD mouse model. GW501516 protected against vascular cell death by inhibiting expression of miR-15a, which directly regulates the antiapoptotic protein Bcl-2. This resulted in increased Bcl-2 protein expression, reduced Golgi fragmentation, and decreased caspase-3 activity, which in turn reduced cerebrovascular permeability and infarct volume in vivo [43]. Although not tested with respect to protection against stroke-induced injury, PPARδ has been shown to promote survival of neurons under stress conditions. Specifically, L-165041 or GW501516 significantly reduced SH-SY5Y cell death after exposure to (i) thapsigargin, an endoplasmic reticulum Ca2+ ATPase inhibitor; (ii) 1-methyl-4-pheylpyridinium (MPP+), a dopaminergic neurotoxin; or (iii) staurosporine, a protein kinase inhibitor. The effect on viability may be due to inhibition of apoptosis, as both agonists could significantly attenuate caspase-3 and caspase-7 activity in cells treated with one of the three cytotoxins [12]. GW0742 has also been shown to be neuroprotective in primary cultures of rat cerebellar granule neurons exposed to low-KCl media. Prolonged exposure of primary cultures to
