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The nitric oxide (NO) system has been proven to be a valuable modulator of L-DOPA-induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second-messenger cGMP. Although we have previously described the anti-dyskinetic potential of NO synthase inhibitors on L-DOPA-induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non-selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), could mitigate L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Here, we demonstrated that methylene blue was able to reduce L-DOPA-induced dyskinesia incidence when chronically co-administered with L-DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L-DOPA-induced dyskinesia in rats rendered dyskinetic by a previous course of L-DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co-administration of methylene blue and L-DOPA for 2 consecutive days followed by vehicle and L-DOPA co-administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L-DOPA-induced dyskinesia. Taken together, these results demonstrate an important role of NO-soluble guanylyl cyclase-cGMP signaling on L-DOPA-induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, the long-term use of L-DOPA causes, in combination with disease progression, the development of motor complications termed L-DOPA-induced dyskinesia (LID). LID is the result of profound modifications in the functional organization of the basal ganglia circuitry. There is increasing evidence of the involvement of non-dopaminergic systems on the pathophysiology of LID. This raises the possibility of novel promising therapeutic approaches in the future, including agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in preclinical testing or clinical development. Herein, we summarize the current knowledge of the pharmacology of LID in PD. More importantly, this review attempts to highlight the role of nitric oxide (NO) in PD and provide a comprehensive picture of recent preclinical findings from our group and others showing its potential involvement in dyskinesia.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic L-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as L-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with L-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of L-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic L-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10-30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1-30 mg/kg) and NG-nitro-L-arginine (50 mg/kg), given 30 min before L-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat L-DOPA-induced dyskinesia.