title: Glial activation is associated with l-DOPA induced dyskinesia and blocked by a nitric oxide synthase inhibitor in a rat model of Parkinson's disease.
abstract: 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.
authors.affiliation: University of São Paulo (USP), School of Odontology of Ribeirao Preto, Department of Morphology, Physiology and Basic Pathology, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil.
authors.forename: Mariza
authors.initials: M
authors.lastname: Bortolanza
authors.affiliation: USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil; USP, Medical School, Department of Physiology, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cavalcanti-Kiwiatkoski
authors.affiliation: USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil; USP, Department of Behavioral Neurosciences, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Padovan-Neto
authors.affiliation: University of São Paulo (USP), School of Odontology of Ribeirao Preto, Department of Morphology, Physiology and Basic Pathology, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil.
authors.forename: Célia Aparecida
authors.initials: CA
authors.lastname: da-Silva
authors.affiliation: Light Microscopy Facility Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany.
authors.forename: Miso
authors.initials: M
authors.lastname: Mitkovski
authors.affiliation: Sorbonne Université UPMC UM75 INSERM U1127, CNRS UMR 7225, Institut de Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.affiliation: University of São Paulo (USP), School of Odontology of Ribeirao Preto, Department of Morphology, Physiology and Basic Pathology, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil; USP, Medical School, Department of Physiology, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil; USP, Department of Behavioral Neurosciences, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil. Electronic address: eadelbel@forp.usp.br.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del-Bel
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009457:Neuroglia / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D000978:Antiparkinson Agents; D007191:Indazoles; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D007980:Levodopa; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole
keywords: 6-OHDA lesion; GFAP; Glial cells; Neuroinflammation; OX-42; iNOS