Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic-ischemic brain injury in rats

BACKGROUND: The endocannabinoids are emerging as natural brain protective substances which exert potentially beneficial effects in several neurological disorders by virtue of their hypothermic, immunomodulatory, vascular, antioxidant and antiapoptotic actions. The present study was undertaken to assess if preventing the deactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG) with the monoacylglycerol lipase (MAGL) inhibitor URB602 can provide neuroprotective effects in hypoxia-ischemia (HI) induced brain injury. METHODS: URB602 was administered into the right lateral ventricle 30 min before 7 day-old pup rats were subjected to HI. The neuroprotective effect was evaluated on postnatal-day (PN) 14 or at adulthood (PN80) using behavioral and histological analyses. Activated caspase-3 expression and propidium iodide (PI) labeling were assessed as indexes of apoptotic and necrotic cell death, respectively. RESULTS: Pretreatment with URB602 reduced both apoptotic and necrotic cell death, as well as the infarct volume measured at PN14. At adulthood, URB602-treated HI animals performed better the T-maze and the Morris maze, and also showed a significant reduction of brain damage. CONCLUSIONS: These results demonstrate that a pretreatment with URB602 significantly reduces brain damage and improves functional outcome indicating that endocannabinoid degrading enzymes may represent an important target for neuroprotection in neonatal ischemic brain injury.