Autophagy in Schwann cells: A potential pharmacotherapeutic target in diabetic peripheral neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes and is characterized by sensory and motor impairments resulting from neural injury. Schwann cells (SCs), which are important for peripheral nerve function, are compromised under hyperglycemic conditions, leading to impaired axonal regeneration and demyelination. Autophagy, a cellular degradation process, is essential for SC function and significantly influences DPN progression. This article highlights the significance of autophagy in SCs and its potential as a pharmacotherapeutic target in DPN. We discuss the mechanisms of autophagy in SCs, including the mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, and phosphatase and tensin homolog-induced putative kinase/parkin pathways, and their dysregulation in DPN. This article also examines various natural products and chemical agents that modulate autophagy and enhance the efficacy of DPN treatment. These agents target key signaling pathways, such as adenosine monophosphate-activated protein kinase/mammalian target of rapamycin and demonstrate potential in promoting nerve regeneration and restoring SC function. The roles of exosomes, long non-coding RNA, and proteins in the regulation of autophagy have also been explored. In conclusion, targeting autophagy in SCs is a promising strategy for DPN treatment and offers new insights into therapeutic interventions. Further research is warranted to fully exploit these targets for clinical applications.

Keywords: Adenosine monophosphate-activated protein kinase; Agent; Autophagy; Diabetic peripheral neuropathy; Mammalian target of rapamycin; Schwann cells.

Figure 1

Autophagic imbalance leads to Schwann cell dysfunction. High glucose-induced oxidative stress triggers reactive oxygen species release, activates protein kinase B via phosphatidylinositol 3-kinase, inhibits tuberous sclerosis complex, and promotes mammalian target of rapamycin phosphorylation. Subsequently mRNA translation is enhanced and autophagosome formation is inhibited. Lysosomal damage induces transforming growth factor-β-activated protein kinase 1-galectin-9 binding, which activates adenosine monophosphate-activated protein kinase and unc-51-like kinase 1 to promote autophagy. Mitochondrial damage under high glucose leads to phosphatase and tensin homolog induced putative kinase 1 accumulation and parkin phosphorylation. AMPK: Adenosine monophosphate-activated protein kinase; mTOR: Mammalian target of rapamycin; PI3K: Phosphatidylinositol 3-kinase; ULK1: Unc-51-like kinase 1; ATG13: Autophagy related 13; FIP200: Focal adhesion kinase family kinase-interacting protein 200kD; ROS: Reactive oxygen species; SQSTM1: Sequestosome 1; LC3: Light chain 3; PINK1: Phosphatase and tensin homolog-induced putative kinase 1.