Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice

Overactivity of the corticostriatal glutamatergic pathway is documented in Parkinson's disease (PD) and stim-ulation of presynaptic metabotropic glutamate (mGlu) receptors 4 on these striatal afferents inhibits glutamate release normalizing neuronal activity in the basal ganglia. Moreover, mGlu4 receptors are also expressed in glial cells and are able to modulate glial function making this receptor a potential target for neuroprotection. Hence, we investigated whether foliglurax, a positive allosteric modulator of mGlu4 receptors with high brain exposure after oral administration, has neuroprotective effects in MPTP mice to model early PD. Male mice were treated daily from day 1 to 10 with 1, 3 or 10 mg/kg of foliglurax and administered MPTP on the 5th day then euthanized on the 11th day. Dopamine neuron integrity was assessed with measures of striatal dopamine and its metabolites levels, striatal and nigral dopamine transporter (DAT) binding and inflammation with markers of striatal astrocytes (GFAP) and microglia (Iba1). MPTP lesion produced a decrease in dopamine, its metabolites and striatal DAT specific binding that was prevented by treatment with 3 mg/kg of foliglurax, whereas 1 and 10 mg/kg had no beneficial effect. MPTP mice had increased levels of GFAP; foliglurax treatment (3 mg/kg) pre-vented this increase. Iba1 levels were unchanged in MPTP mice compared to control mice. There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD.

Automated summary

Overactivity of the corticostriatal glutamatergic pathway is found in Parkinson's disease (PD). Stimulation of presynaptic metabotropic glutamate (mGlu) receptors 4 inhibits glutamate release and normalizes neuronal activity in the basal ganglia. mGlu4 receptors in glial cells can also modulate glial function, making them a potential target for neuroprotection. In this study, the positive allosteric modulator of mGlu4 receptors, foliglurax, showed neuroprotective effects in the MPTP mouse model of PD.