title: Differential pattern of motor impairments in neurotoxic, environmental and inflammation-driven rat models of Parkinson's disease.
abstract: One of the reasons proposed for the paucity of drug discovery for Parkinson's disease is the lack of relevant animal models of the condition. Parkinson's disease has been modelled extensively using the selective neurotoxin, 6-hydroxydopamine (6-OHDA). However, as this model bears little etiological resemblance to the human condition, there has been a drive to develop models with improved etiological validity. Two such models are those induced by the pesticide, rotenone, and the inflammagen, lipopolysaccharide (LPS). However, to date, these models have been poorly characterised in terms of their motor profiles and have never been directly compared to the more established models. Thus, the aim of this study was to characterise the behavioural profile of the rotenone and LPS models, and to compare them with the 6-OHDA model. Animals underwent baseline testing on the Stepping, Whisker, Corridor and Cylinder Tests of motor function. They were then grouped for unilateral intra-striatal infusion of 6-OHDA, rotenone or LPS. Motor testing continued for ten weeks after which the rats were processed for immunohistochemical analysis of nigrostriatal integrity. We found that, although all neurotoxins induced a similar level of nigrostriatal neurodegeneration, neither the rotenone nor LPS models were associated with amphetamine-induced rotation, and they were associated with significantly less pronounced and stable impairments in the spontaneous tasks than the 6-OHDA model. In conclusion, this study demonstrates key differences in the pattern of motor dysfunction induced by Parkinsonian neurotoxins which should be taken into consideration when selecting the most appropriate model for Parkinson's disease preclinical studies.
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: Naughton
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Moriarty
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Feehan
authors.affiliation: School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address: eilis.dowd@nuigalway.ie.
authors.forename: Eilís
authors.initials: E
authors.lastname: Dowd
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D016627:Oxidopamine / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity*
chemical_list: D008070:Lipopolysaccharides; D009498:Neurotoxins; D012402:Rotenone; D016627:Oxidopamine
keywords: 6-Hydroxydopamine; Animal models; Lipopolysaccharide; Parkinson’s disease; Rotenone