Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy.

Abstract

Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKβ and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKβ-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKβ-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.

• Authors: You Chul Chung, Ji Hee Lim, Hyun Mi Oh, Hyung Wook Kim, Min Young Kim, Eun Nim Kim, Yaeni Kim, Yoon Sik Chang, Hye Won Kim, Cheol Whee Park
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 12 Pg. 1163 (11 26 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 30478254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nitric Oxide Synthase Type III
• Protein Kinases
• Protein Serine-Threonine Kinases
• STK11 protein, human
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinase Kinases
• Cinacalcet

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (genetics)
• Cinacalcet (pharmacology)
• Diabetic Neuropathies (drug therapy, genetics, pathology)
• Gene Expression Regulation (drug effects)
• Humans
• Mice
• Mice, Inbred NOD
• Nerve Degeneration (drug therapy, genetics, pathology)
• Nitric Oxide Synthase Type III (genetics)
• Oxidative Stress (drug effects)
• Peripheral Nervous System Diseases (drug therapy, genetics, pathology)
• Protein Kinases (genetics)
• Protein Serine-Threonine Kinases (genetics)
• Schwann Cells (drug effects, pathology)
• Sciatic Nerve (drug effects, pathology)
• Signal Transduction (drug effects)