Prolonged blockade of NMDA or mGluR5 glutamate receptors reduces nigrostriatal degeneration while inducing selective metabolic changes in the basal ganglia circuitry in a rodent model of Parkinson's disease

• Published in: Neurobiology of disease 2006-04, Vol.22 (1), p.1-9
• Main Authors: Armentero, Marie-Thérèse, Fancellu, Roberto, Nappi, Giuseppe, Bramanti, Placido, Blandini, Fabio
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Animals; Basal ganglia; Cell Survival - drug effects; Cell Survival - physiology; Corpus Striatum - drug effects; Corpus Striatum - pathology; Corpus Striatum - physiopathology; Cytochrome oxidase; Disease Models, Animal; Dizocilpine Maleate - pharmacology; Dizocilpine Maleate - therapeutic use; Electron Transport Complex IV - drug effects; Electron Transport Complex IV - metabolism; Energy Metabolism - drug effects; Energy Metabolism - physiology; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Amino Acid Antagonists - therapeutic use; Ionotropic; Male; Metabotropic; Nerve Degeneration - drug therapy; Nerve Degeneration - physiopathology; Nerve Degeneration - prevention & control; Neural Pathways - drug effects; Neural Pathways - pathology; Neural Pathways - physiopathology; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidopamine; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Pyridines - pharmacology; Pyridines - therapeutic use; Rat; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Glutamate - drug effects; Receptors, Glutamate - metabolism; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Striatum; Substantia nigra; Substantia Nigra - drug effects; Substantia Nigra - pathology; Substantia Nigra - physiopathology; Subthalamic Nucleus - drug effects; Subthalamic Nucleus - metabolism; Subthalamic Nucleus - physiopathology; Tyrosine hydroxylase
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2005.09.010

We compared the neuroprotective and metabolic effects of chronic treatment with ionotropic or metabotropic glutamate receptor antagonists, in rats bearing a unilateral nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). The ionotropic, N-methyl- d-aspartate receptor antagonist MK-801 increased cell survival in the substantia nigra pars compacta (SNc) and corrected the metabolic hyperactivity (increased cytochrome oxidase activity) of the ipsilateral substantia nigra pars reticulata (SNr) associated with the lesion, but showed no effects on the 6-OHDA-induced hyperactivity of the subthalamic nucleus (STN). Significant—although less pronounced—protection of SNc neurons was also observed following treatment with the metabotropic glutamate receptor (mGluR5) antagonist 2-methyl-6-(phenylehtynyl)-pyridine (MPEP). As opposed to MK-801, MPEP abolished the STN metabolic hyperactivity associated with the nigrostriatal lesion, without affecting SNr activity. Specific modulation of STN hyperactivity obtained with mGluR5 blockade may, therefore, open interesting perspectives for the use of this class of compounds in the treatment of Parkinson's disease.