Ciliary neurotrophic factor activates NF-?B to enhance mitochondrial
bioenergetics and prevent neuropathy in sensory neurons of
streptozotocin-induced diabetic rodents.
Authors Saleh A, Roy Chowdhury SK, Smith DR, Balakrishnan S, Tessler L, Martens C,
Morrow D, Schartner E, Frizzi KE, Calcutt NA, Fernyhough P
Submitted By Nigel Calcutt on 1/30/2013
Status Published
Journal Neuropharmacology
Year 2013
Date Published 2/1/2013
Volume : Pages 65 : 65 - 73
PubMed Reference 23022047
Abstract Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute
to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory
neuron survival and axon regeneration and prevents axonal dwindling, nerve
conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we
tested the hypothesis that CNTF protects sensory neuron function during diabetes
through normalization of impaired mitochondrial bioenergetics. In addition, we
investigated whether the NF-?B signal transduction pathway was mobilized by
CNTF. Neurite outgrowth of sensory neurons derived from streptozotocin
(STZ)-induced diabetic rats was reduced compared to neurons from control rats
and exposure to CNTF for 24 h enhanced neurite outgrowth. CNTF also activated
NF-?B, as assessed by Western blotting for the NF-?B p50 subunit and reporter
assays for NF-?B promoter activity. Conversely, blockade of NF-?B signaling
using SN50 peptide inhibited CNTF-mediated neurite outgrowth. Studies in mice
with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented
functional indices of peripheral neuropathy along with deficiencies in dorsal
root ganglion (DRG) NF-?B p50 expression and DNA binding activity. DRG neurons
derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen
consumption rate and associated spare respiratory capacity that were corrected
by exposure to CNTF for 24 h in an NF-?B-dependent manner. We propose that the
ability of CNTF to enhance axon regeneration and protect peripheral nerve from
structural and functional indices of diabetic peripheral neuropathy is
associated with targeting of mitochondrial function, in part via NF-?B
activation, and improvement of cellular bioenergetics.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego