The Protective Effects of Pre-Treatment with Glutamate Metabotropic Receptor Agonists on the Development of Parkinsonian Movements

Abstract

The subcortical nuclei of the basal ganglia are of great importance in initiation of normal body motor activities. Degeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta has been shown to be the main cause of Parkinson’s disease (PD) (Phillips & Brown, 1999; Phillips et al., 2006; and Truong et al., 2006). Degeneration of dopaminergic neurons within the nigrostriatal pathway following treatment with the neurotoxin 6-hydroxy dopamine (6-OHDA) has been accepted widely as a good model of PD (Wichmann et al., 2002; Willis & Kennedy, 2004; Vernon et al., 2005; Troung et al., 2006; Chaturvedi et al., 2006; Phillips et al., 2006). Excitatory amino acids play an important role, not only in epilepsy (Coutinhio-Netto et al., 1981; Bradford 1995; Abdul-Ghani et al 1997) but also in some neurodegenerative diseases (Wilkinski & Acosta 1995). Excitation of sub-thalamic nucleus neurons in vitro was achieved by activation of group I metabotropic glutamate receptors by (S,R)-dihydroxy-phenylglycine (DHPG), and was blocked by the receptor antagonist (+)-alpha-methyl-4carboxyphenylglycine (MCPG). No effects were obtained with the selective agonists of group II and group III metabotropic receptors such as L-2-amino-4-phosphonobutyrate (LAP4) and (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine ( DCG-IV) (Abbott et al., 1997). Intra-sub-thalamic injection of (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R)-ACPD produced marked contra-lateral rotation, similar to that seen after intrastriatal injection of (1S,3S)-ACPD, suggesting that metabotropic glutamate receptors as a possible target for the treatment of Parkinson's disease (Sacaan et al., 1991: 1992; Kaatz & Albin, 1995). Further more Group-III mGlu receptors stimulation by LAP4 was found to improve akinesia in a rat model of Parkinson's disease (Cuomo et al., 2009). Recently attention has focused on seeking alternative non-dopaminergic strategies in the treatment of basal ganglia disorders, and is now shifting to glutamatergic pathways. In the current experiments we have tested the effect of pre-treatment with a glutamate metabotropic receptor agonist Sub-type III, LAP4 and a glutamate metabotropic receptor antagonist, MPPG, injected into the median forebrain bundle or to the striatum, on rats