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首页> 外文期刊>The European Journal of Neuroscience >Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington's disease.
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Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington's disease.

机译：IV型磷酸二酯酶抑制作用可防止CREB结合蛋白被隔离，保护纹状体小白蛋白中间神经元并挽救亨廷顿氏病R6 / 2小鼠模型的运动功能障碍。

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The phosphodiesterase type IV inhibitor rolipram increases cAMP response element-binding protein (CREB) phosphorylation and exerts neuroprotective effects in both the quinolinic acid rat model of Huntington's disease (DeMarch et al., 2007) and the R6/2 mouse including sparing of striatal neurons, prevention of neuronal intranuclear inclusion formation and attenuation of microglial reaction (DeMarch et al., 2008). In this study, we sought to determine if rolipram has a beneficial role in the altered distribution of CREB binding protein in striatal spiny neurons and in the motor impairments shown by R6/2 mutants. Moreover, we investigated whether rolipram treatment altered the degeneration of parvalbuminergic interneurons typical of Huntington's disease (Fusco et al., 1999). Transgenic mice and their wild-type controls from a stable colony maintained in our laboratory were treated with rolipram (1.5 mg/kg) or saline daily starting from 4 weeks of age. The cellular distribution of CREB binding protein in striatal spiny neurons was assessed by immunofluorescence, whereas parvalbuminergic neuron degeneration was evaluated by cell counts of immunohistochemically labeled tissue. Motor coordination and motor activity were also examined. We found that rolipram was effective in preventing CREB binding protein sequestration into striatal neuronal intranuclear inclusions, sparing parvalbuminergic interneurons of R6/2 mice, and rescuing their motor coordination and motor activity deficits. Our findings demonstrate the possibility of reversing pharmacologically the behavioral and neuropathological abnormalities of symptomatic R6/2 mice and underline the potential therapeutic value of phosphodiesterase type IV inhibitors in Huntington's disease.
机译：磷酸二酯酶IV型抑制剂咯利普兰在亨廷顿氏病的喹啉酸大鼠模型（DeMarch等，2007）和R6 / 2小鼠（包括纹状体神经元）中均增加了cAMP反应元件结合蛋白（CREB）的磷酸化并发挥了神经保护作用。 ，防止神经元核内包涵体形成和小胶质细胞反应的减弱（DeMarch等，2008）。在这项研究中，我们试图确定咯利普兰是否在改变纹状体棘神经元中CREB结合蛋白的分布以及R6 / 2突变体显示的运动障碍中具有有益作用。此外，我们研究了咯利普兰治疗是否改变了亨廷顿氏病典型的小白蛋白能中神经元的变性（Fusco等，1999）。从4周龄开始，每天使用咯利普兰（1.5 mg / kg）或生理盐水处理来自我们实验室中稳定种群的转基因小鼠及其野生型对照。通过免疫荧光评估纹状体棘神经元中CREB结合蛋白的细胞分布，而通过免疫组织化学标记组织的细胞计数评估小白蛋白能神经元变性。运动协调和运动活动也进行了检查。我们发现，咯利普兰可以有效地防止CREB结合蛋白螯合到纹状体神经元核内包涵体中，保留R6 / 2小鼠的小白蛋白能中间神经元，并拯救它们的运动协调和运动活性不足。我们的发现表明，在药理学上逆转有症状的R6 / 2小鼠的行为和神经病理学异常的可能性，并强调了磷酸二酯酶IV型抑制剂在亨廷顿氏病中的潜在治疗价值。

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