Received for publication May 26, 2006.
Revised September 28, 2006.
Accepted for publication September 28, 2006.

Selective activation of Group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutyric acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo

Abstract

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 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 here report that both acute and sub-chronic 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 co-administration of the selective Group III mGluR antagonist (RS)--methylserine-O-phosphate (MSOP) 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, which may have important implications for the future treatment of this disease.

Key words: 6-hydroxydopamine, Dopamine, Glutamate, Neuroprotection, Parkinson's disease, metabotropic glutamate receptor