title: Antidyskinetic Effect of 7-Nitroindazole and Sodium Nitroprusside Associated with Amantadine in a Rat Model of Parkinson's Disease.
abstract: Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.
authors.affiliation: Department of Morphology, Physiology and Basic Pathology, School of Odontology, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14040-904, Brazil.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Prêto, Brazil.
authors.forename: Mariza
authors.initials: M
authors.lastname: Bortolanza
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Prêto, Brazil.|Department of Behavioural Neuroscience, Medical School, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14049-900, Brazil.
authors.forename: Keila D
authors.initials: KD
authors.lastname: Bariotto-Dos-Santos
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Prêto, Brazil.|Department of Physiology, Medical School, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14049-900, Brazil.
authors.forename: Maurício
authors.initials: M
authors.lastname: Dos-Santos-Pereira
authors.affiliation: Department of Morphology, Physiology and Basic Pathology, School of Odontology, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14040-904, Brazil.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Prêto, Brazil.
authors.forename: Célia Aparecida
authors.initials: CA
authors.lastname: da-Silva
authors.affiliation: Department of Morphology, Physiology and Basic Pathology, School of Odontology, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14040-904, Brazil. eadelbel@forp.usp.br.|Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, Ribeirão Prêto, Brazil. eadelbel@forp.usp.br.|Department of Behavioural Neuroscience, Medical School, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14049-900, Brazil. eadelbel@forp.usp.br.|Department of Physiology, Medical School, University of Sao Paulo (USP), Campus Ribeirao Preto, Ribeirao Preto, SP, 14049-900, Brazil. eadelbel@forp.usp.br.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del-Bel
mesh_terms: D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000150:complications* / Q000188:drug therapy*; D007191:Indazoles / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects; D008845:Microinjections; D009599:Nitroprusside / Q000627:therapeutic use*; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy*; D051381:Rats
chemical_list: D007191:Indazoles; D009599:Nitroprusside; D007980:Levodopa; D016627:Oxidopamine; D000547:Amantadine; C080122:7-nitroindazole
keywords: Abnormal involuntary movements; Dopamine; Glutamate; L-DOPA-induced dyskinesia; Nitric oxide