NEW evidences for fractalkine/CX3CL1 involved in substantia nigral microglial activation and behavioral changes in a rat model of Parkinson's disease

Activated microglia are instrumental to neurodegeneration in Parkinson's disease (PD). Fractalkine, as an exclusive ligand for CX3CR1 expressed on microglia, has recently been reported to be released out by neurons, and induce microglial activation as a neuron-to-glia signal in the spinal cord. However, the role of fractalkine-induced microglial activation in PD remains unknown. In our study, we injected 1-methyl-4-phenylpyridinium (MPP+) into unilateral substantia nigra (SN) which induced ipsilateral endogenous fractalkine expression on neuron and observe the increase of CX3CR1 expression in response to MPP+ by Western blotting analysis. Moreover, pre-administration of anti-CX3CR1 neutralizing antibody which potentially blocked microglial activation can promote rotation behaviors. To further investigate the role of fractalkine in PD, we injected exogenous fractalkine in unilateral SN, and observed microglial activation, dopaminergic cell depletion, and motor dysfunction. All these effects can be totally abolished by cerebroventricular administration of anti-CX3CR1. Intracerebroventricular administration of minocycline, a selective microglia inhibitor, can prevent fractalkine-induced rotation behaviors, and inhibit dopaminergic neurons from degeneration in the way of dose-dependent. Our studies demonstrate that fractalkine-induced microglial activation plays an important role in the development of PD, and provide an evidence of fractalkine and CX3CR1 as new therapeutic targets for PD treatment. (C) 2009 Elsevier Inc. All rights reserved.