No abstract

This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN.

Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease related neuropathy, reconnection of axons to their targets is required to restore function. Supporting peripheral axon regrowth, while not yet available in clinics, might be accomplished from several directions focusing on one or more of the complex stages of regrowth. Direct axon support, with follow on participation of supporting Schwann cells is one approach, emphasized in this review. However alternative approaches might include direct support of Schwann cells that instruct axons to regrow, manipulation of the inflammatory milieu to prevent ongoing bystander axon damage, or use of inflammatory cytokines as growth factors. Axons may be supported by a growing list of growth factors, extending well beyond the classical neurotrophin family. The understanding of growth factor roles continues to expand but their impact experimentally and in humans has faced serious limitations. The downstream signaling pathways that impact neuron growth have been exploited less frequently in regeneration models and rarely in human work, despite their promise and potency. Here we review the major regenerative signaling cascades that are known to influence adult peripheral axon regeneration. Within these pathways there are major checkpoints or roadblocks that normally check unwanted growth, but are an impediment to robust growth after injury. Several molecular roadblocks, overlapping with tumour suppressor systems in oncology, operate at the level of the perikarya. They have impacts on overall neuron plasticity and growth. A second approach targets proteins that largely operate at growth cones. Addressing both sites might offer synergistic benefits to regrowing neurons. This review emphasizes intrinsic aspects of adult peripheral axon regeneration, emphasizing several molecular barriers to regrowth that have been studied in our laboratory.