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Titolo:
Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata
Autore:
Staal, RGW; Sonsalla, PK;
Indirizzi:
Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, Piscataway, NJ 08854 USA Univ Med & Dent New Jersey Piscataway NJ USA 08854 scataway, NJ 08854 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 293, anno: 2000,
pagine: 336 - 342
SICI:
0022-3565(200005)293:2<336:IOBVMT>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPAMINERGIC NEUROTOXICITY; CHROMAFFIN GRANULES; SPECIES SENSITIVITY; CELLULAR-RESISTANCE; MPTP NEUROTOXICITY; AMINE TRANSPORTER; KNOCKOUT MICE; IN-VIVO; TOXICITY; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Sonsalla, PK Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, DeptNeurol, 675 Hoes Lane, Piscataway, NJ 08854 USA Univ Med & Dent New Jersey675 Hoes Lane Piscataway NJ USA 08854
Citazione:
R.G.W. Staal e P.K. Sonsalla, "Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata", J PHARM EXP, 293(2), 2000, pp. 336-342

Abstract

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP+, suggesting a larger storage capacity for MPP+ in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP+ in vivo. Dose-response curvesfor striatally infused MPP+ were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP+ dose-response curve and a significant lowering of the EC50 concentration for MPP+-induced damage. These findings provide evidence for a substantial accumulation of MPP+ in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP+ sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP+ or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP+ may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP+ toxicity in the rat, the potency of MPP+ in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP+ toxicity in the mouse or attenuate MPP+ toxicity in rats.

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Documento generato il 13/07/20 alle ore 04:48:18