Effects of calpain inhibition on dopaminergic markers and motor function following intrastriatal 6-hydroxydopamine administration in rats |
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Authors: | R.J. Grant L.H.L. Sellings S.J. Crocker E. Melloni D.S. Park P.B.S. Clarke |
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Affiliation: | 1. Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler Room 1325, Montreal, Quebec, Canada H3G 1Y6;2. Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA;3. Department of Experimental Medicine, University of Genoa, 1-16132 Genoa, Italy;4. Neuroscience Research Group, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 |
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Abstract: | The neurotoxin 6-hydroxydopamine has been widely used to model aspects of Parkinson's disease in rodents, but the mechanisms underlying toxin-induced dopaminergic degeneration and functional impairment have not been fully elucidated. The main aim of the present study was to assess a possible role for calpains in neurochemical and behavioral deficits following unilateral infusion of intrastriatal 6-hydroxydopamine in adult rats. Toxin administration produced a profound dopaminergic denervation, as indicated by a 90–95% reduction in dopamine transporter radiolabeling measured in the caudate-putamen at 2 weeks post-lesion. Treatment with 6-hydroxydopamine also resulted in calpain activation in both caudate-putamen and substantia nigra, as measured by the appearance of calpain-specific spectrin breakdown products. Calpain activation peaked at 24 h after 6-hydroxydopamine infusion and remained elevated at later time points. In contrast, caspase-3-mediated spectrin cleavage subsided within 48 h in both brain areas. In a subsequent experiment, calpain inhibition was achieved by intrastriatal infusion of an adenovirus expressing the endogenous calpain inhibitor, calpastatin. Calpastatin delivery abolished the lesion-induced calpain-mediated spectrin cleavage and alleviated forelimb asymmetries resulting from unilateral intrastriatal 6-hydroxydopamine. Unexpectedly, dopamine transporter and tyrosine hydroxylase labeling revealed significant neuroprotection, not in the nigrostriatal pathway but rather in the ventral tegmental area. These findings support a role for calpain activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. However, after near-total dopaminergic depletion, the primary benefit of calpain inhibition may not occur within the nigrostriatal dopaminergic pathway itself. |
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Keywords: | calpastatin caspase dopamine 6-hydroxydopamine motor striatum |
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