Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata.
Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata.
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发表时间：
2000-05
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通讯作者：
Roland G. W. Staal;P. Sonsalla
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作者：
Roland G. W. Staal;P. Sonsalla
不同动物的多巴胺神经元对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）或1-甲基-4-苯基吡啶（MPP（+））的神经毒性的敏感性不同。与小鼠分离的纹状体囊泡相比，大鼠分离的纹状体囊泡具有更高的脑囊泡单胺转运体（VMAT 2）密度和更强的隔离MPP（+）的能力，表明大鼠囊泡中MPP（+）的储存容量更大。在目前的研究中，我们研究了纹状体VMAT 2囊泡是否可以提供保护，对MPP（+）的神经毒性作用在体内。在用或不用VMAT 2抑制剂预处理的动物中测定纹状体输注MPP（+）的剂量-反应曲线。Ro 4-1284给药（10 mg/kg i. p.; VMAT 2抑制剂）使MPP（+）剂量-反应曲线发生5倍的位移，并显著降低MPP（+）诱导的损伤的EC（50）浓度。这些发现为MPP（+）在大鼠纹状体中体内含有VMAT 2的囊泡中的大量积累提供了证据，并支持了MPP（+）在囊泡中的隔离可以提供对其毒性作用的保护的假设。在小鼠中，VMAT 2抑制并不能可靠地增强MPP（+）纹状体输注或MPTP全身给药产生的毒性。这些数据表明，MPP（+）的囊泡隔离在小鼠中的重要性可能低于在大鼠中的保护作用。目前的结果还表明，虽然VMAT 2抑制增强大鼠纹状体MPP（+）的毒性，MPP（+）在大鼠纹状体的效力低于小鼠纹状体。这意味着还有其他因素可以加剧小鼠中MPP（+）毒性或减弱大鼠中MPP（+）毒性。
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.