Modulating Molecular Chaperones Improves Mitochondrial
Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic
Sensory Neurons
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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 2β20 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