title: Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons.
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.
authors.affiliation: Department of Pharmacology and Toxicology and ‡̂Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology and ‡̂Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.affiliation: Department of Pharmacology and Toxicology and ‡̂Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Mercy
authors.initials: M
authors.lastname: Anyika
authors.affiliation: Department of Pharmacology and Toxicology and ‡̂Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.affiliation: Department of Pharmacology and Toxicology and ‡̂Department of Medicinal Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Rick T
authors.initials: RT
authors.lastname: Dobrowsky
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006027:Glycosides / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008159:Lumbar Vertebrae; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D006027:Glycosides; D018840:HSP70 Heat-Shock Proteins; C000608218:KU-596; D018696:Neuroprotective Agents; D010627:Phenethylamines; D017382:Reactive Oxygen Species
keywords: Bioenergetics; RNA Seq; diabetic neuropathy; inflammation; molecular chaperones; oxidative stress