Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective.

Objectives: Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP.

Evidence acquisition: A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019.

Results: DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP.

Conclusion: The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .