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首页> 外文期刊>The European Journal of Neuroscience >Protein tyrosine phosphatase inhibition reduces degeneration of dopaminergic substantia nigra neurons and projections in 6-OHDA treated adult rats.
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Protein tyrosine phosphatase inhibition reduces degeneration of dopaminergic substantia nigra neurons and projections in 6-OHDA treated adult rats.

机译：蛋白质酪氨酸磷酸酶抑制作用可以减少多巴胺能黑质神经元的变性和6-OHDA处理的成年大鼠的投射。

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摘要

The survival of injured adult dopaminergic substantia nigra pars compacta neurons can be promoted by various neurotrophic factors. Most neurotrophic factor receptors are activated by intracellular tyrosine phosphorylation upon ligand binding and are subsequently inactivated or dephosphorylated by protein tyrosine phosphatases. This raised the possibility that tyrosine phosphatase inhibition might improve neuronal survival. Here, we infused the stable water-soluble tyrosine phosphatase-specific inhibitor, peroxovanadium [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) (bpV(phen))], for 14 days close to the substantia nigra starting immediately after a unilateral moderate injury by injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the midbrain of adult Sprague-Dawley rats. The dopaminergic nigrostriatal neurons were identified by retrograde tracing with fluorogold 7 days prior to the injury. With infusion of 3 or 10 microm peroxovanadium, 75% of these neurons survived compared to 45% invehicle-infused rats. Degeneration of the dopaminergic projections to the neostriatum was also reduced by 10 microm peroxovanadium. Twenty minutes after an acute injection of peroxovanadium into the substantia nigra, increased tyrosine phosphorylation in Western blots of nigral extracts was seen in the same protein bands as after injections of brain-derived neurotrophic factor (BDNF) or NT-4. This suggests that peroxovanadium enhances endogenous neurotrophic signalling resulting in improved neuronal survival. The neuroprotective effects of this small molecule protein tyrosine phosphatase inhibitor represent a proof-of-principle for a novel treatment strategy in a model for Parkinson's disease.
机译：各种神经营养因子可促进受伤的成人多巴胺能黑质致密神经元的存活。大多数神经营养因子受体在配体结合后通过细胞内酪氨酸磷酸化被激活，随后被蛋白质酪氨酸磷酸酶灭活或去磷酸化。这增加了酪氨酸磷酸酶抑制可能改善神经元存活的可能性。在这里，我们注入了一种稳定的水溶性酪氨酸磷酸酶特异性抑制剂过氧钒[bisperoxo（1,10-菲咯啉）氧钒酸钾（V）（bpV（phen））]，持续14天，距黑质致死后立即开始。通过向成年Sprague-Dawley大鼠的中脑注射神经毒素6-羟基多巴胺（6-OHDA）进行单方面中度损伤。在损伤前7天，通过用荧光金逆行示踪来鉴定多巴胺能黑质纹状体神经元。输注3或10微米过氧钒后，这些神经元中的75％得以存活，而注入车辆的大鼠为45％。多巴胺能投射到新纹状体的变性也减少了10微米过氧钒。在向黑质中急性注射过氧钒后二十分钟，在与注射脑源性神经营养因子（BDNF）或NT-4相同的蛋白带中，发现黑质提取物的蛋白质印迹中酪氨酸磷酸化增加。这表明过氧钒可增强内源性神经营养信号，从而改善神经元存活率。这种小分子蛋白酪氨酸磷酸酶抑制剂的神经保护作用代表了帕金森氏病模型中新型治疗策略的原理证明。

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