Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons
Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons
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DOI：
10.1021/acschemneuro.5b00165
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发表时间：
2015-09-01
影响因子：
5
通讯作者：
Dobrowsky, Rick T.
中科院分区：
文献类型：
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作者：
Ma, Jiacheng;Pan, Pan;Dobrowsky, Rick T.
我们之前已经证明，调节带有KU-32（一种新生物素衍生物）的分子伴侣可以改善糖尿病周围神经病变（DPN）的生理和生物能量缺陷。用间氟联苯环系统取代KU-32的香豆素核心，产生了KU-596，这是一种新生物素类似物（novologue），在基于细胞的实验中显示出神经保护活性。目前的研究试图确定KU-596是否在治疗DPN方面具有类似的治疗潜力。给药2- 20mg /kg KU-596以剂量依赖的方式改善糖尿病诱导的痛觉减退和感觉神经元生物能量缺陷。然而，该药物不能改善糖尿病热休克蛋白70敲除（Hsp70 KO）小鼠的这些神经性缺陷。为了进一步了解KU-596改善DPN的机制，我们使用RNA测序对糖尿病野生型和Hsp70 KO小鼠的感觉神经元RNA进行了转录组学分析。差异表达基因的生物信息学分析表明，糖尿病强烈地增加了炎症途径，KU-596治疗有效地逆转了这些增加，不依赖于Hsp70。相反，KU-596对降低活性氧产生调控基因表达的作用更依赖于hsp70。这些数据表明，通过新疗法调节分子伴侣为纠正DPN的神经功能障碍提供了一种有效的方法，但仅通过新疗法使炎症通路正常化似乎不足以逆转与无感觉DPN相关的感觉缺陷。
We have previously demonstrated that modulating molecular chaperones with KU-32, a novobiocin derivative, ameliorates physiologic and bioenergetic deficits of diabetic peripheral neuropathy (DPN). Replacing the coumarin core of KU-32 with a meta-fluorinated biphenyl ring system created KU-596, a novobiocin analogue (novologue) that showed neuroprotective activity in a cell-based assay. The current study sought to determine whether KU-596 offers similar therapeutic potential for treating DPN. Administration of 2-20 mg/kg of KU-596 improved diabetes induced hypoalgesia and sensory neuron bioenergetic deficits in a dose-dependent manner. However, the drug could not improve these neuropathic deficits in diabetic heat shock protein 70 knockout (Hsp70 KO) mice. To gain further insight into the mechanisms by which KU-596 improved DPN, we performed transcriptomic analysis of sensory neuron RNA obtained from diabetic wild-type and Hsp70 KO mice using RNA sequencing. Bioinformatic analysis of the differentially expressed genes indicated that diabetes strongly increased inflammatory pathways and that KU-596 therapy effectively reversed these increases independent of Hsp70. In contrast, the effects of KU-596 on decreasing the expression of genes regulating the production of reactive oxygen species were more Hsp70-dependent. These data indicate that modulation of molecular chaperones by novologue therapy offers an effective approach toward correcting nerve dysfunction in DPN but that normalization of inflammatory pathways alone by novologue therapy seems to be insufficient to reverse sensory deficits associated with insensate DPN.