title: Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat.
abstract: The pathogenesis of Parkinson's disease is thought to involve a self-sustaining cycle of neuroinflammation and neurodegeneration. In order to develop novel anti-inflammatory therapies to break this cycle, it is crucial that the temporal relationship between neurodegeneration and neuroinflammation is characterised in pre-clinical models to maximise their predictive validity. Thus, this study aimed to investigate the progression of neuroinflammation relative to nigrostriatal neurodegeneration in the two most commonly-used rat models of Parkinson's disease. Male Sprague-Dawley rats were lesioned by terminal or axonal administration of 6-hydroxydopamine, and were sacrificed for quantitative immunohistochemistry (to assess nigrostriatal integrity (anti-tyrosine hydroxylase), microgliosis (anti-OX42) and astrocytosis (anti-GFAP)) at 6 h 24 h 72 h or 2 weeks post-lesion. Following terminal lesion, dopaminergic deafferentation of the striatum was evident from 6 h post-lesion and was accompanied by microglial and astroglial activation. Dopamine neuron loss from the substantia nigra did not occur until 2 weeks after terminal lesion, and this was preceded by microglial, but not astroglial, activation. Following axonal lesion, retraction of nigrostriatal terminals from the striatum was not observed until the 72 h time-point, and this was associated with a slight astrocytosis, but not microgliosis. Degeneration of dopaminergic neurons from the substantia nigra was also evident from 72 h after axonal lesion, and was accompanied by nigral microgliosis and astrocytosis by 2 weeks. This study highlights the temporal relationship between neurodegeneration and neuroinflammation in models of Parkinson's disease, and should facilitate use of these models in the development of anti-inflammatory therapies for the human condition.
authors.affiliation: Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Walsh
authors.forename: D P
authors.initials: DP
authors.lastname: Finn
authors.forename: E
authors.initials: E
authors.lastname: Dowd
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009411:Nerve Endings / Q000187:drug effects / Q000473:pathology*; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D016627:Oxidopamine