Ciliary neurotrophic factor activates NF-κB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents

• Published in: Neuropharmacology Vol. 65; pp. 65 - 73
• Main Authors: Saleh, Ali, Roy Chowdhury, Subir K., Smith, Darrell R., Balakrishnan, Savitha, Tessler, Lori, Martens, Corina, Morrow, Dwane, Schartner, Emily, Frizzi, Katie E., Calcutt, Nigel A., Fernyhough, Paul
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2013
• Subjects: Animals; Axon regeneration; Bioenergetics profile; Cells, Cultured; Ciliary Neurotrophic Factor - pharmacology; Ciliary Neurotrophic Factor - therapeutic use; CNTF; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - prevention & control; Diabetic neuropathy; Dorsal root ganglia; Energy Metabolism - drug effects; Energy Metabolism - physiology; Female; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; NF-kappa B - metabolism; NF-κB; Oxidative phosphorylation; Rats; Rats, Sprague-Dawley; Respiration; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; Sensory Receptor Cells - pathology; NF-κB; CNTF; Dorsal root ganglia; Oxidative phosphorylation; Axon regeneration; Diabetic neuropathy; Bioenergetics profile; Diabetes; Respiration
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.09.015

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-κB 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-κB, as assessed by Western blotting for the NF-κB p50 subunit and reporter assays for NF-κB promoter activity. Conversely, blockade of NF-κB 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-κB 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-κB-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-κB activation, and improvement of cellular bioenergetics. ► Test hypothesis that CNTF modulates mitochondrial function. ► Study of sensory neurons in diabetic neuropathy. ► CNTF increased regeneration via NF-κB activity. ► CNTF treatment of diabetic mice prevented neuropathy and normalized deficient NF-κB. ► CNTF treatment of diabetic neurons optimized mitochondrial function via NF-κB.