Staal R G, Sonsalla P K
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-4535, USA.
J Pharmacol Exp Ther. 2000 May;293(2):336-42.
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 curves for 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 EC(50) 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.
来自不同动物物种的多巴胺神经元对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）或1-甲基-4-苯基吡啶鎓（MPP(+)）的神经毒性敏感性不同。与从小鼠分离的纹状体囊泡相比，大鼠的纹状体囊泡具有更高密度的脑囊泡单胺转运体（VMAT2）以及更强的隔离MPP(+)的能力，这表明大鼠囊泡对MPP(+)具有更大的储存容量。在本研究中，我们检测了含纹状体VMAT2的囊泡是否能在体内提供针对MPP(+)神经毒性作用的保护。在用或不用VMAT2抑制剂预处理的动物中，测定纹状体注入MPP(+)的剂量-反应曲线。给予Ro 4-1284（10 mg/kg腹腔注射；VMAT2抑制剂）使MPP(+)剂量-反应曲线向左移位5倍，并显著降低MPP(+)诱导损伤的EC(50)浓度。这些发现为大鼠纹状体中含VMAT2的囊泡在体内大量蓄积MPP(+)提供了证据，并支持囊泡中MPP(+)的隔离可针对其毒性作用提供保护这一假说。在小鼠中，VMAT2抑制并不能可靠地增强纹状体注入MPP(+)或全身给予MPTP所产生的毒性。这些数据表明，就免受毒素影响而言，MPP(+)的囊泡隔离在小鼠中可能不如在大鼠中重要。本研究结果还表明，虽然VMAT2抑制增强了大鼠纹状体中MPP(+)的毒性，但MPP(+)在大鼠纹状体中的效力低于在小鼠纹状体中的效力。这意味着存在其他因素，要么加剧小鼠中MPP(+)的毒性，要么减弱大鼠中MPP(+)的毒性。
