Parkin-Knockout Mice did not Display Increased Vulnerability to Intranasal Administration of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Neurotoxicity Research - Tập 24 - Trang 280-287 - 2013
Aderbal S. Aguiar1, Fabrine S. M. Tristão2, Majid Amar2, Caroline Chevarin3, Laurence Lanfumey3, Raymond Mongeau3, Olga Corti2, Rui D. Prediger1, Rita Raisman-Vozari2
1Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil
2INSERM UMR 975 (ex U679)—CNRS UMR 7225, Hôpital de la Salpêtrière—Bâtiment, ICM (Centre de Recheche de l’Institut du Cerveau et de la Moelle épinière), CRICM, Thérapeutique Expérimentale de la Neurodégénérescence, Université Pierre et Marie Curie, UPMC, Paris, France
3INSERM UMR S894, Centre de Psychiatrie et Neuroscience, Université Pierre et Marie Curie (UPMC), Paris, France

Tóm tắt

The loss of nigral dopaminergic neurons in Parkinson’s disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, the hybrid 129Sv-C57BL/6 parkin-deficient mice did not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to neurotoxicity induced by 6-hydroxydopamine (6-OHDA) or intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We aimed to re-evaluate the role of parkin in a pure C57BL/6 background after an acute intranasal (i.n.) MPTP administration, a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. We found that the deficiency of parkin gene modifies the d-amphetamine-induced locomotion in saline-treated animals. Intranasal MPTP induced Parkinsonism in parkin+/+ mice, through depletion of striatal dopamine, decreased number of dopaminergic neurons in the substantia nigra, and decreased d-amphetamine-induced hyperlocomotion. Additionally, the deletion of the parkin gene in a pure C57BL/6 background did not lead to increased vulnerability to i.n. MPTP-induced neurotoxicity. Moreover, the i.n. MPTP induced nigral astrogliosis predominantly in the pars reticulata in wild type and parkin−/− mice. Taken together, these results showed that the absence of parkin did not modify the vulnerability of nigrostriatal dopaminergic pathway after i.n. MPTP intoxication, suggesting that independently of mouse strain, the endogenous parkin is not required for protection of this system. These findings also suggest that the development of familial parkin-linked PD is not associated with exposure to environmental factors that specifically affects the dopaminergic system.

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