Activation of Group III Metabotropic Glutamate Receptors Attenuates Rotenone Toxicity on Dopaminergic Neurons through a Microtubule-Dependent Mechanism

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Abstract
Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral dopaminergic (DA) neurons and Parkinson’s disease-like symptoms in animal models. Our previous study has shown that the microtubule-depolymerizing activity of rotenone plays a critical role in its selective toxicity on tyrosine hydroxylase-positive (TH+) neurons in rat embryonic midbrain neuronal cultures. Here, we show that application of group III metabotropic glutamate receptor (mGluRIII) agonists (e.g., l-AP-4) significantly reduced rotenone toxicity on midbrain TH+ neurons in culture. The protective effect of l-AP-4 was abolished by pharmacological inhibition of the microtubule-associated protein (MAP) kinase kinase (MEK) or overexpression of dominant-negative MEK1, suggesting its dependence on the MAP kinase cascade. We found that l-AP-4 induced a rapid and transient activation of the MAP kinase extracellular signal-regulated kinase (ERK) through a pathway mediated by dynamin, β-arrestin 2, and Src. ERK activated in this manner targeted cytosolic rather than nuclear substrates. Consistent with this, l-AP-4 significantly attenuated rotenone- or colchicine-induced microtubule depolymerization in an MEK-dependent manner. Moreover, l-AP-4 decreased colchicine toxicity on TH+ neurons in an MEK-dependent manner as well. The protective effect of l-AP-4 against rotenone toxicity was occluded by the microtubule-stabilizing agent Taxol. Together, these results suggest that activation of group III metabotropic glutamate receptors attenuates the selective toxicity of rotenone on DA neurons by activating the MAP kinase pathway to stabilize microtubules. These findings may offer a novel neuroprotective approach against rotenone-induced parkinsonism.