title: Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic-ischemic brain injury in rats.
abstract: BACKGROUND
  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.
  
  
  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 labeling were assessed as indexes of apoptotic and necrotic cell death, respectively.
  
  
  RESULTS
  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.
  
  
  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.
authors: Department of Biomolecular Sciences, Section of Pharmacology and Pharmacognosy, University of Urbino Carlo Bo, Urbino (PU), Italy.
authors: Silvia
authors: S
authors: Carloni
authors: Daniel
authors: D
authors: Alonso-Alconada
authors: Silvia
authors: S
authors: Girelli
authors: Andrea
authors: A
authors: Duranti
authors: Andrea
authors: A
authors: Tontini
authors: Daniele
authors: D
authors: Piomelli
authors: Enrique
authors: E
authors: Hilario
authors: Antonia
authors: A
authors: Alvarez
authors: Walter
authors: W
authors: Balduini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005989:Glycerides / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D007276:Injections, Intraventricular; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009336:Necrosis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D018696:Neuroprotective Agents; C501835:URB602; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C505410:Casp3 protein, rat; D053148:Caspase 3