Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons
Year: 2015
Type: article
Abstract: 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.
Source: ACS Chemical Neuroscience
Institution: University of Kansas
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2578633385, G2853296776, G3958390639, Chaperones in Diabetic Peripheral Neuropathy, Chaperone therapeutics for the treatment of DPN, Coordinating and Bioinformatics Unit for the MMPC/DiaComp, G6062732923, G6142126022, G6486379080, Molecular Analysis of Disease Pathways, G7050361831, Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors, HSP90 Inhibitors, Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors, Kansas IDeA Network of Biomedical Research Excellence 5
OpenAlex ID: W2439195794