Concurrent mGlu<sub>2</sub>-mGlu<sub>4</sub> receptor positive allosteric modulation for L-DOPA-induced treatment-induced complications in the parkinsonian marmoset.

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

The treatment of advanced Parkinson's disease (PD) remains challenging, with few options to address motor fluctuations and dyskinesia simultaneously. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors may be a therapeutic option that could alleviate both fluctuations and dyskinesia. mGlu4 receptors form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, suggesting that additive anti-parkinsonian and antidyskinetic could be obtained upon dual mGlu2-mGlu4 positive allosteric modulation. Here, the mGlu2 positive allosteric modulator (PAM) LY-487,379 and the mGlu4 PAM ADX-88178 were administered, either alone or together, in combination with L-3,4-dihydroxyphenylalanine (L-DOPA), to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, after which the severity of parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) was assessed. We discovered that each of LY-487,379 and ADX-88178 enhanced the anti-parkinsonian action of L-DOPA and reduced dyskinesia severity when administered separately; when administered concurrently, the resulting anti-parkinsonian (P 2-mGlu4 positive allosteric modulation results in greater anti-parkinsonian and anti-dyskinetic effects than positive allosteric modulation of either target separately. In addition dual mGlu2-mGlu4 positive allosteric modulation enhances the anti-psychotic effect of selective mGlu2 positive allosteric modulation. Concurrent mGlu2-mGlu4 positive allosteric modulation represents a promising avenue for the treatment of complications in advanced PD.

Related topics