Neuroprotective effects of metabotropic glutamate receptor ligands in a 6-hydroxydopamine rodent model of Parkinson's disease.
Increasing evidence implicates glutamate-mediated excitotoxicity as a contributory factor in dopaminergic cell death in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD). Previous studies have suggested that metabotropic glutamate receptor (mGluR) ligands are neuroprotective against excitotoxicity in vitro. In the present study, the neurotoxin 6-hydroxydopamine (6-OHDA) produced a significant loss (61.2 +/- 8.9%; P < 0.01) of tyrosine hydroxylase-immunopositive (TH+) cells in both the SNc and striatal dopamine (58.02 +/- 1.27%; P < 0.05) in control male Sprague-Dawley rats. Both losses were significantly attenuated by sub-chronic (7 day) treatment with the Group I mGluR antagonists, 2-methyl-6(phenylethynyl)-pyridine (MPEP) or (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385); the Group II mGluR agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC); or the Group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4). These data demonstrate a neuroprotective action of mGluR ligands in vivo against 6-OHDA toxicity that has important implications for the treatment of PD.
Vernon
A C
AC
Parkinson's Disease Research Group, Department of Cellular and Molecular Neuroscience, Faculty of Medicine, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK.
Palmer
S
S
Datla
K P
KP
Zbarsky
V
V
Croucher
M J
MJ
Dexter
D T
DT
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D007839:Functional Laterality / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013565:Sympatholytics / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase