Aim: 

Previously, using mGlu2/3 metabotropic glutamate receptor agonist LY379268 we evidenced an increase of GDNF protein levels in the mouse striatum and a protective action against nigro-striatal damage in the mouse MPTP model. In mice lacking either mGlu2 or mGlu3 receptors we could also show that treatment with LY379268 enhances GDNF levels in wild-type and mGlu2-/- mice, but not in mGlu3-/- mice, leading to the conclusion that GDNF increases in response to mGlu3 receptor activation. In the present work, in order to correlate the GDNF increase with its involvement on the neuroprotection observed after mGlu3 receptor activation, since GDNF-mediated activation of c-RET initiates signal transduction pathways, we aimed to examine the protein and phosphorylation levels of mitogen-activated protein kinases (ERK1/2) and serine-threonine kinase (AKT) in the striatum.

Methods: 

Using two doses of LY379268 (0.25 and 2 mg/kg, i.p.), both able to enhance GDNF, a time-course study was performed and the activation or protein levels of ERK1/2 and AKT were evaluated by western blotting.

Results: 

After 24h of acute treatment with LY379268 the levels ERK1/2, but not AKT, were significantly activated in the mouse striatum, whereas their protein levels were unchanged. This activation of ERK1/2 was time-related to GDNF upregulation, suggesting an involvement of c-ret activation.

Conclusion: 

The data suggest that mGlu receptor agonists by GDNF/c-ret neurotrophic system activation are potential candidates as neuroprotective agents in Parkinson's disease.