Neuroprotective effects of N-acetylaspartylglutamate in a neonatal rat model of hypoxia-ischemia.
Neuroprotective effects of N-acetylaspartylglutamate (NAAG), the precursor of glutamate and a selective agonist at the Group II metabotropic glutamate (mGlu) receptor, against hypoxic-ischemic brain injury were examined in a neonatal rat model of cerebral hypoxia-ischemia. The neonatal hypoxia-ischemia procedure (unilateral carotid artery ligation followed by exposure to an 8% oxygen hypoxic condition for 1.5 h) was performed in 7-day-old rat pups. Following unilateral carotid artery ligation, NAAG (0.5 to 20 mg/kg, i.p.) was administered before or after the hypoxic exposure. Brain injury was examined 1-week later by weight reduction in the ipsilateral brain and by neuron density in the hippocampal CA1 area. In the saline-treated rat, neonatal hypoxia-ischemia resulted in severe brain injury as indicated by a 24% reduction in the ipsilateral brain weight. Low doses of NAAG (2-10 mg/kg, but not 0.5 mg/kg), administered before or even if 1 h after the hypoxic exposure, greatly reduced hypoxia-ischemia-induced brain injury (3.8-14.2% reduction in the ipsilateral brain weight). A high dose of NAAG (20 mg/kg) was ineffective. While L(+)-2-Amino-4-phosphonobutyric acid (L-AP4) and trans-[1S,3R]-1-Amino-cyclopentane-1, 3-dicarboxylic acid (t-ACPD) were unable to provide protection against hypoxic-ischemic brain injury, 2-(phosphonomethyl) pentanedioic acid (2-PMPA), an inhibitor of N-acetylated alpha-linked acidic dipeptidase (NAALADase), which hydrolyzes endogenous NAAG into N-acetyl-aspartate and glutamate, significantly reduced neonatal hypoxia-ischemia-induced brain injury. (alphaS)-alpha-Amino-alpha-[(1S, 2S)-2-carboxycyclopropyl]-9H-xanthine-9-propanoic acid (LY341495), a selective antagonist at the mGlu2/3 receptor, prevented the neuroprotective effect of NAAG. Neuron density data measured in the hippocampal CA1 area confirmed that ipsilateral brain weight reduction was a valid measure for hypoxic-ischemic brain injury. Neonatal hypoxia-ischemia stimulated an elevation of cyclic AMP (cAMP) concentration in the saline-treated rat brain. NAAG, L-AP4 and t-ACPD all significantly decreased hypoxia-ischemia-induced elevation of cAMP. LY341495 blocked the effect of NAAG, but not of L-AP4 or t-ACPD, on hypoxia-ischemia-stimulated cAMP elevation. The overall results suggest that the neuroprotective effect of NAAG is largely associated with activation of mGlu2/3 receptor.
Cai
Zhengwei
Z
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. zcai@ped.umsmed.edu
Lin
Shuying
S
Rhodes
Philip G
PG
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014966:Xanthenes / Q000494:pharmacology
C402107:2-(phosphonomethyl)pentanedioic acid; C114785:2-amino-4-phosphono-propinate; D000596:Amino Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D011422:Propionates; D014966:Xanthenes; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C027172:isospaglumic acid; D000242:Cyclic AMP; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II