Therapeutic potential of metabotropic glutamate receptor 4-positive allosteric modulator TAS-4 in rodent models of movement disorders

Parkinson's disease (PD) is a very serious neurological disorder, and current methods of treatment fail to achieve long-term control. Previous studies suggest that stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. In the present study, we describe the pharmacological characterization of an mGluR4 PAM, N-(2, 4-dichlorophenyl) pyridine-2-carboxamide (TAS-4), in several rodent PD models. TAS-4 is a potent and selective mGluR4 PAM of the human mGluR4 receptor (EC₅₀- 287.8nM). TAS-4 showed efficacy alone or when administered in combination with l-DOPA. When administered alone, TAS-4 exhibited efficacy in reversing haloperidol-induced catalepsy. In addition, acute TAS-4 dose-dependently potentiated contralateral turning behavior induced by a threshold dose of l-3,4-dihydroxyphenylalanine (l-DOPA, 4mg/kg i.p.), a classical test for antiparkinson drug screening. Subchronic (28days, twice a day) TAS-4 (10mg/kg i.p.)+l-DOPA (4mg/kg i.p.) did not induce sensitization to turning behavior or abnormal involuntary movements during the course of treatment. Moreover, subchronic administration of a fully effective dose of l-DOPA (8mg/kg i.p.) significantly induces sensitization to turning behavior or abnormal involuntary movements. Results showed that TAS-4, in association with a low dose of l-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of l-DOPA without exacerbating abnormal motor side effects.

6-OHDA (6-hydroxydopamine); Abnormal involuntary movements; Metabotropic glutamate receptor 4-positive allosteric modulator (mGluR4 PAM); Parkinson's disease (PD); TAS-4; l-DOPA (levodopa).