Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy.
Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy.
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DOI：
10.1016/j.expneurol.2012.03.005
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发表时间：
2012-05
影响因子：
5.3
通讯作者：
Dobrowsky, Rick T.
中科院分区：
文献类型：
--
作者：
Urban, Michael J.;Pan, Pan;Farmer, Kevin L.;Zhao, Huiping;Blagg, Brian S. J.;Dobrowsky, Rick T.
关键词：
表皮内神经纤维 (iENF) 的定量是糖尿病周围神经病变 (DPN) 分期的重要方法，也是确定有益治疗方法的有前景的临床终点。从机制上讲，糖尿病会降低神经元线粒体功能，增强线粒体呼吸能力可能有助于神经元从糖毒损伤中恢复。我们提出调节热休克蛋白 (Hsp) 的活性和表达可能有助于治疗 DPN。 KU-32 是一种 C 端 Hsp90 抑制剂，可改善糖尿病 C57Bl/6 小鼠的热痛觉减退，但尚未确定这是否与 iENF 密度和线粒体功能的增加有关。患有糖尿病 16 周后，瑞士韦伯斯特小鼠表现出电生理和心理感觉反应下降，iENF 损失超过 30%。小鼠每周接受 10 次 20 mg/kg KU-32 治疗，显着逆转了先前存在的神经传导速度以及对机械和热刺激反应的缺陷。 KU-32 疗法显着逆转了先前存在的 iENF 损失，尽管经过药物治疗的糖尿病小鼠亚组的鉴定显示热敏感性有所改善，但 iENF 密度没有增加。为了确定临床指标的改善是否与线粒体活性的增强相关，分离了感觉神经元，并使用细胞外通量技术对线粒体生物能进行离体评估。糖尿病降低了感觉神经元的最大呼吸能力，并且这种缺陷在 KU-32 治疗后得到了改善。总之，KU-32 改善了退行性神经病的生理和形态标志物，并且药物疗效可能与感觉神经元中线粒体生物能的增强有关。
Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20 mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons.
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影响因子：
7.4
作者：
Dranka, Brian P.;Hill, Bradford G.;Darley-Usmar, Victor M.
通讯作者：
Darley-Usmar, Victor M.
DOI：
10.1523/jneurosci.3347-10.2011
发表时间：
2011-02-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Courchesne SL;Karch C;Pazyra-Murphy MF;Segal RA
通讯作者：
Segal RA
影响因子：
3.6
作者：
Huang, Yung-Tzung;Blagg, Brian S. J.
通讯作者：
Blagg, Brian S. J.
影响因子：
2.9
作者：
Guzhova, I;Kislyakova, K;Margulis, B
通讯作者：
Margulis, B
DOI：
10.1073/pnas.0705799105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Chung, Jason;Nguyen, Anh-Khoi;Febbraio, Mark A.
通讯作者：
Febbraio, Mark A.