Neuroprotective Efficacy of the Peroxisome Proliferator-Activated Receptor δ-Selective Agonists in Vitro and in Vivo

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and function as ligandmodulated transcription factors that regulate gene expression in many important biological processes. The PPAR␦ subtype has the highest expression in the brain and is postulated to play a major role in neuronal cell function; however, the precise physiological roles of this receptor remain to be elucidated. Herein, we show that the high-affinity PPAR␦ agonists L-165041 [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxyl]phenoxy]-acetic acid] and GW501516 [2-methyl4-((4 -methyl-2-(4-trifluoromethylphenyl) -1,3 -triazol-5-yl)-methylsulfanyl)phenoxy acetic acid] protect against cytotoxininduced SH-SY5Y cell injury in vitro and both ischemic brain injury and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in vivo. In the SH-SY5Y studies, treatment with L-165041 or GW501516 significantly and concentrationdependently attenuated cell death following thapsigargin, 1-methyl-4-phenylpyridinium, or staurosporine exposure, with the extent of damage correlated with the level of caspase-3 inhibition. In the transient (90 min) middle cerebral artery occlusion model of ischemic brain injury in rats, i.c.v. infusion of L-165041 or GW501516 significantly attenuated the ischemic brain damage measured 24 h after reperfusion. Moreover, the PPAR␦ agonists also significantly attenuated MPTP-induced depletion of striatal dopamine and related metabolite contents in mouse brain. These results demonstrate that subtypeselective PPAR␦ agonists possess antiapoptotic properties in vitro, which may underlie their potential neuroprotective potential in in vivo experimental models of cerebral ischemia and Parkinson's disease (PD). These findings suggest that PPAR␦ agonists could be useful tools for understanding the role of PPAR␦ in other neurodegenerative disorders, as well as attractive therapeutic candidates for stroke and neurodegenerative diseases such as PD.

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

“…The beneficial role of PPAR / in stroke has been demonstrated by two different studies in which PPAR / knockout mice subjected to cerebral IRI showed significantly larger infarct size than wild-type littermates (Pialat, Cho et al 2007). This finding is confirmed by another study demonstrating that intracerebroventricular administration of high affinity PPAR / agonists such as L-165041 and GW501516 significantly decreased the infarct volume at 24 h of reperfusion after cerebral ischemia in rats (Iwashita, Muramatsu et al 2007). …”

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…In cultured cardiomyocytes, PPAR-delta/beta agonist GW0742 inhibited LPS-induced TNF-alpha secretion, while the absence of PPAR-delta/beta further increased TNF-alpha secretion (109). Intracerebroventricular administration of high affinity PPAR-delta/beta agonists such as L-165041 and GW501516 significantly decreased the infarct volume at 24h of reperfusion after cerebral ischemia in rats (110). Furthermore, PPAR-delta/beta agonists prevented the loss of striatal dopamine after MPTP administration, suggesting that PPAR-delta/beta could serve as a potential therapeutic target in several CNS diseases (110).…”

Neuroprotection by dietary restriction and the PPAR transcription complex

“…Despite its relative novelty, several reports have already indicated neuroprotective effects of PPAR-delta in models of Alzheimer's disease [95], stroke [96,97], and Parkinson's disease [96].…”