glyceryl-2-arachidonate and Hypoxia-Ischemia--Brain

The endocannabinoids are emerging as natural brain protective substances that exert potentially beneficial effects in several neurological disorders by virtue of their hypothermic, immunomodulatory, vascular, antioxidant, and antiapoptotic actions. This study was undertaken to assess whether 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.. 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 labeling were assessed as indexes of apoptotic and necrotic cell death, respectively.. Pretreatment with URB602 reduced apoptotic and necrotic cell death, as well as the infarct volume measured at PN14. At adulthood, URB602-treated HI animals performed better at the T-maze and the Morris maze, and also showed a significant reduction of brain damage.. 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.

Topics: Animals; Animals, Newborn; Apoptosis; Arachidonic Acids; Behavior, Animal; Biphenyl Compounds; Brain; Caspase 3; Disease Models, Animal; Endocannabinoids; Enzyme Activation; Enzyme Inhibitors; Female; Glycerides; Hypoxia-Ischemia, Brain; Injections, Intraventricular; Monoacylglycerol Lipases; Necrosis; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Time Factors

Hypoxic-ischemic (HI) insult during the perinatal period remains as one of the most common causes of brain injury and produces long-term neurological deficits, and there is a growing need for effective therapies. The aim of the present work was to perform a prospective study designed to assess the possible protector effect of two endocannabinoids: 2-arachidonoylglycerol (2AG) and anandamide (AEA) in the brain after HI injury in perinatal rat model. We evaluate their effects on cell death and check several cellular parameters. 7-days-old Wistar rats were assigned to four different experimental groups (n=7-10): Sham, HI, and HI treated with 2AG or AEA. The injury was induced by the left carotid artery ligature and subsequent exposure to 8% O(2) for 120 min. Immediately after the injury, treated groups received a single dose of 2AG (1mg/kg) or AEA (5mg/kg) and then animals were sacrificed 24, 72 h or 7 days after the HI event. Brains fixed by perfusion were stained with Nissl for morphological studies, and non-fixed brains were dissociated and analyzed by flow cytometry to quantify apoptosis, mitochondrial state, intracellular calcium and reactive oxygen species. Our results show that both 2AG and AEA have beneficial effects after HI injury in this rat model, producing a remarkable amelioration of brain injury, reducing apoptotic cell death, contributing to the maintenance of mitochondrial functionality, and improving cellular parameters such as the influx of calcium and ROS production.

Topics: Animals; Animals, Newborn; Apoptosis; Arachidonic Acids; Endocannabinoids; Flow Cytometry; Glycerides; Hypoxia-Ischemia, Brain; Mitochondria; Neuroprotective Agents; Oxidative Stress; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reactive Oxygen Species