l-3, 4-dihydroxyphenylalanine (
L-DOPA) is the most effective treatment for
Parkinson's disease but can induce debilitating abnormal
involuntary movements (
dyskinesia). Here we show that the development of
L-DOPA-induced
dyskinesia in the rat is accompanied by upregulation of an inflammatory cascade involving
nitric oxide. Male Wistar rats sustained unilateral
injections of
6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. After three weeks animals started to receive daily treatment with
L-DOPA (30 mg/kg plus
benserazide 7.5 mg/kg, for 21 days), combined with an inhibitor of neuronal NOS (7-nitroindazole, 7-NI, 30 mg/kg/day) or vehicle (saline-PEG 50%). All animals treated with
L-DOPA and vehicle developed abnormal
involuntary movements, and this effect was prevented by 7-NI.
L-DOPA-treated dyskinetic animals exhibited an increased striatal and pallidal expression of
glial fibrillary acidic protein (GFAP) in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and the rise of cells positive for
inducible nitric oxide-synthase immunoreactivity (iNOS). All these indexes of glial activation were prevented by 7-NI co-administration. These findings provide evidence that the development of
L-DOPA-induced
dyskinesia in the rat is associated with activation of glial cells that promote inflammatory responses. The dramatic effect of 7-NI in preventing this glial response points to an involvement of
nitric oxide. Moreover, the results suggest that the NOS inhibitor prevents
dyskinesia at least in part via inhibition of glial cell activation and iNOS expression. Our observations indicate
nitric oxide synthase inhibitors as a therapeutic strategy for preventing neuroinflammatory and glial components of
dyskinesia pathogenesis in
Parkinson's disease.