Effects of calpain inhibition on dopaminergic markers and motor function following intrastriatal 6-hydroxydopamine administration in rats.
Neuroscience
; 158(2): 558-69, 2009 Jan 23.
Article
em En
| MEDLINE
| ID: mdl-19007862
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Calpaína
/
Dopamina
/
Oxidopamina
/
Adrenérgicos
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Corpo Estriado
/
Atividade Motora
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neuroscience
Ano de publicação:
2009
Tipo de documento:
Article