Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons.
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.
['Ma|Jiacheng|J|', 'Pan|Pan|P|', 'Anyika|Mercy|M|', 'Blagg|Brian S J|BS|', 'Dobrowsky|Rick T|RT|']
D000818:Animals D003921:Diabetes Mellitus, Experimental D003929:Diabetic Neuropathies D004305:Dose-Response Relationship, Drug D004734:Energy Metabolism D005260:Female D005727:Ganglia, Spinal D006027:Glycosides D018840:HSP70 Heat-Shock Proteins D008159:Lumbar Vertebrae D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D018696:Neuroprotective Agents D018384:Oxidative Stress D010146:Pain D010627:Phenethylamines D017382:Reactive Oxygen Species D011984:Sensory Receptor Cells D059467:Transcriptome
molecular chaperones Bioenergetics RNA Seq diabetic neuropathy inflammation oxidative stress