Impaired Axonal Regeneration in Diabetes. Perspective on the Underlying Mechanism from In Vivo and In Vitro Experimental Studies

Abstract

Axonal regeneration after peripheral nerve injury is impaired in diabetes, but its precise mechanisms have not been elucidated. In this paper, we summarize the progress of research on altered axonal regeneration in animal models of diabetes and cultured nerve tissues exposed to hyperglycemia. Impaired nerve regeneration in animal diabetes can be attributed to dysfunction of neurons and Schwann cells, unfavorable stromal environment supportive of regenerating axons, and alterations of target tissues receptive to reinnervation. In particular, there are a number of factors such as enhanced activity of the negative regulators of axonal regeneration (e.g., phosphatase and tensin homolog deleted on chromosome 10 and Rho/Rho kinase), delayed Wallerian degeneration, alterations of the extracellular matrix components, enhanced binding of advanced glycation endproducts (AGEs) with the receptor for AGE, and delayed muscle reinnervation that can be obstacles to functional recovery after an axonal injury. It is also noteworthy that we and others have observed excessive neurite outgrowth from peripheral sensory ganglion explants from streptozotocin (STZ)-diabetic mice in culture and enhanced regeneration of small nerve fibers after sciatic nerve injury in STZ-induced diabetic rats. The excess of abortive neurite outgrowth may lead to misconnections of axons and target organs, which may interfere with appropriate target reinnervation and functional repair. Amelioration of perturbed nerve regeneration may be crucial for the future management of diabetic neuropathy.

Diabetes Mellitus-Related Dysfunction of the Motor System

“…This is considered an important causative factor of the proximodistal phenotype of DN. Impaired axonal transport, coupled with dysfunction in Schwann cells and other cells, also affects the delay in peripheral nerve regeneration due to diabetes [ 84 ]. The pathogenesis of axonal transport dysfunction is known to involve multiple mechanisms, including protein aggregation, excitotoxicity, oxidative stress, mitochondrial dysfunction, inflammation, and defects in axonal transport [ 85 ].…”

Zonisamide enhances neurite outgrowth from adult rat dorsal root ganglion neurons, but not proliferation or migration of Schwann cells

“…Second, individual neurons are isolated from other neurons and non-neuronal cells in vitro, and the effects of cellular interplay on axonal regeneration cannot be evaluated. To overcome these defects, we have established a three-dimensional culture system of ganglion explants in which adult peripheral ganglia with nerve fibers are embedded in collagen gel or Matrigel ® , and neurite outgrowth from transected nerve stump has been evaluated (Horie et al 1994;Sango et al 2017). Because of the maintenance of cell-to-cell interactions, it may be reasonable to consider that the explant culture mimics axonal regeneration in vivo better than the use of dissociated cells.…”

“…Successful axonal regeneration in the peripheral nervous system (PNS) depends on the capacity of neurons and/or Schwann cells to regenerate neurites, the environment distal to the injury, and the target tissues receptive to reinnervation (Sango et al 2017). The sequence of cellular events during Wallerian degeneration includes Schwann cell activation and proliferation, macrophage recruitment, elimination of axonal and myelin debris, and synthesis of neurotrophic and chemotactic factors.…”

Strategies to improve nerve regeneration after radical prostatectomy: a narrative review

“…About co-morbidity, it is well know that axonal regeneration following peripheral nerve injury is impaired in diabetic patients and has been documented in experimental diabetic animal models: diabetic conditions induce alterations in the biological properties of neurons and Schwann cells leading to delay in Wallerian degeneration and macrophage infiltration, furthermore reduce the expression of neurotrophic factors and alteration of the extracellular matrix components resulting in impairment of axonal regeneration [48,49].…”