title: Neuroprotective effects of NMDA and group I metabotropic glutamate receptor antagonists against neurodegeneration induced by homocysteine in rat hippocampus: in vivo study.
abstract: Homocysteine (Hcy), a neurotoxic amino acid, is a risk factor for neurodegenerative diseases. Previous in vitro studies have demonstrated that group I metabotropic glutamate receptors along with N-methyl-D-aspartic acid (NMDA) receptors participate in acute and chronic aspects of Hcy-induced neuronal damage. In the present study, we examined whether the same mechanism may be involved in homocysteine neurotoxicity in vivo. Memantine, MPEP, and LY367385 were used as NMDA, mGlu5, and mGlu1 antagonists, respectively. Repeated i.c.v injection of Hcy was performed for three consecutive days. Neuronal loss in different zones of the hippocampus was assessed by Nissl, Fluoro-Jade B, and TUNEL staining. Neuronal degeneration was observed in both types of apoptosis and necrosis. All glutamate receptor antagonists, even when given alone, provided some degree of neuroprotection. The degree of protection was dependent on the area of the hippocampus. While memantine was more potent against Hcy-induced apoptosis, the potency of mGluR antagonists in neuronal protection against apoptosis and necrosis was almost equal. No more protection was observed when all three antagonists were used simultaneously. It seems that Fluoro-Jade could be a useful marker of apoptotic cell death. Taken together, results demonstrate that, in vivo, Hcy neurotoxicity is mediated mainly by the NMDA receptors and group I mGluRs.
authors.affiliation: Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: F
authors.initials: F
authors.lastname: Yeganeh
authors.forename: F
authors.initials: F
authors.lastname: Nikbakht
authors.forename: S
authors.initials: S
authors.lastname: Bahmanpour
authors.forename: K
authors.initials: K
authors.lastname: Rastegar
authors.forename: R
authors.initials: R
authors.lastname: Namavar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006710:Homocysteine / Q000633:toxicity*; D008297:Male; D008559:Memantine / Q000494:pharmacology; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine; D008559:Memantine
references.citation: Int J Radiat Biol. 1992 Apr;61(4):451-3
references.pmid: 1349327
references.citation: Proc Natl Acad Sci U S A. 1997 May 27;94(11):5923-8
references.pmid: 9159176
references.citation: Neurochem Res. 2003 Feb;28(2):259-69
references.pmid: 12608699
references.citation: Age Ageing. 2007 May;36(3):339-43
references.pmid: 17363393
references.citation: Neurochem Int. 2003 Sep-Oct;43(4-5):481-92
references.pmid: 12742095
references.citation: Cardiovasc Res. 2000 Feb;45(3):528-37
references.pmid: 10728374
references.citation: Neurobiol Dis. 2000 Aug;7(4):332-42
references.pmid: 10964605
references.citation: J Neurosci. 2000 Sep 15;20(18):6920-6
references.pmid: 10995836
references.citation: J Comp Neurol. 1996 Mar 11;366(3):516-33
references.pmid: 8907362
references.citation: Acta Neurobiol Exp (Wars). 2006;66(4):301-9
references.pmid: 17265692
references.citation: Neurosci Behav Physiol. 2009 May;39(4):353-62
references.pmid: 19340578
references.citation: Neurotoxicology. 2005 Jun;26(3):361-71
references.pmid: 15935208
references.citation: Biochem Biophys Res Commun. 1995 Feb 6;207(1):40-7
references.pmid: 7857295
references.citation: Acta Neurobiol Exp (Wars). 2004;64(2):153-62
references.pmid: 15366248
references.citation: J Neurosci Res. 2002 Dec 1;70(5):694-702
references.pmid: 12424737
references.citation: Annu Rev Pharmacol Toxicol. 1981;21:165-204
references.pmid: 6112965
references.citation: Hepatology. 1995 May;21(5):1465-8
references.pmid: 7737654
references.citation: J Neurosci. 1999 Nov 15;19(22):RC39
references.pmid: 10559429
references.citation: Adv Biochem Psychopharmacol. 1983;37:163-74
references.pmid: 6314755
references.citation: Brain Res. 1997 Mar 14;751(1):37-46
references.pmid: 9098566
references.citation: Neurosci Lett. 1996 Sep 27;216(2):117-20
references.pmid: 8904797
references.citation: J Neurochem. 2001 Jul;78(2):249-53
references.pmid: 11461960
references.citation: J Comp Neurol. 2000 Nov 20;427(3):440-54
references.pmid: 11054705