Promoting Neuronal Tolerance of Diabetic Stress

Abstract

The etiology of diabetic peripheral neuropathy (DPN) involves an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have targeted proteins and pathways regarded as “diabetes specific” as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. In a complex, chronic neurodegenerative disease such as DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove sufficiently beneficial to pharmacologically enhance the activity of endogenous cytoprotective pathways to aid neuronal tolerance to and recovery from glucotoxic stress. In pursuing this paradigm shift, we have shown that modulating the activity and expression of molecular chaperones such as heat shock protein 70 (Hsp70) may provide translational potential for the effective medical management of insensate DPN. Considerable evidence supports that modulating Hsp70 has beneficial effects in improving inflammation, oxidative stress and glucose sensitivity. Given the emerging potential of modulating Hsp70 to manage DPN, the current review discusses efforts to characterize the cytoprotective effects of this protein and the benefits and limitations that may arise in drug development efforts that exploit its cytoprotective activity.

Alfalfa-derived HSP70 administered intranasally improves insulin sensitivity in mice

“…The potential for aHSP70 to serve as a treatment for T2DM and AD is great (Emery and Dobrowsky, 2016). That source may have advantages over recombinant human protein preparations because it can be produced in large quantities at lower cost and is categorized as a derivative of a natural food product by regulatory agencies.…”

Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice

“…In fact, as of now, the only recommendation for preventing or slowing the progression of peripheral neuropathy is to maintain close glycemic control. It has also been suggested that pharmacological activation of protective neuronal circuits may be useful for increasing tolerance to the hyperglycemic condition and for promoting neuronal recovery [44].…”