It is possible that modulation of these processes contributes to the protective effect of PPARδ after cerebral ischemia. In an in vivo model of MCAO, for example, there was an increase in the lipid peroxidation marker, malondialdehyde, and a decrease in the levels of the antioxidant, glutathione, and the antioxidant enzyme, manganese (Mn)SOD, in PPARδ-null mice compared to WT mice. This suggests that there is increased oxidative stress in PPARδ-null mice following cerebral ischemia [18]. Additionally, mice with PPARδ specifically deleted in their VSMCs had a significant increase in proinflammatory mediators in their brain 24 h after MCAO. This included an increase in the mRNA levels of interleukin-1 beta (IL-1β), IL-6, intercellular adhesion molecule-1 (ICAM-1), and MCP-1 [13]. Pioglitazone, a PPARγ agonist, has been shown to confer neuroprotection following MCAO. This is thought to occur, in part, by activation of PPARδ, which enhances production of the IL-1 receptor antagonist (IL-1Ra). IL-1Ra promotes neuroprotection by competing with binding of IL-1β to IL-1R1; consequently, this represses receptor signaling and reduces inflammatory responses following ischemia [42].
