Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo.
Evidence from several studies suggests that the progressive degeneration of dopaminergic (DA) neurones of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) may in part be due to excessive release of glutamate from subthalamic projections onto nigral DA neurones. Previous in vitro studies have demonstrated that selective activation of Group III metabotropic glutamate receptors (mGluR) negatively modulates excitatory transmission in the SNc and is neuroprotective against glutamate-mediated toxicity. Consistent with this, we have reported preliminary data indicating that the selective group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) can also protect the nigrostriatal system against 6-hydroxydopamine (6-OHDA) toxicity in vivo. We have now extended these preliminary studies in this model and report here that both acute and subchronic intranigral injections of l-AP4 provide significant protection of the nigrostriatal system against 6-OHDA toxicity. This neuroprotection displays a bell-shaped profile with a clear concentration-dependent relationship. In contrast, when administered to animals 7 days post-6-OHDA lesioning, l-AP4 significantly protects the functionality but not the integrity of the nigrostriatal system. We further demonstrate that neuroprotection by l-AP4 in vivo is reversed by coadministration of the selective Group III mGluR antagonist (RS)-alpha-methylserine-O-phosphate, confirming a receptor-mediated mechanism of action. These data provide further compelling evidence that selective activation of Group III mGluR is neuroprotective in an in vivo experimental model of PD, a finding that may have important implications for the future treatment of this disease.
Vernon
Anthony C
AC
Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
Zbarsky
Virginia
V
Datla
Krishna P
KP
Dexter
David T
DT
Croucher
Martin J
MJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D006719:Homovanillic Acid / Q000032:analysis; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D010768:Phosphoserine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000613:Aminobutyrates; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; C120877:methylserine phosphate; D015102:3,4-Dihydroxyphenylacetic Acid; D010768:Phosphoserine; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; C012729:2-amino-4-phosphonobutyric acid; D006719:Homovanillic Acid