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ABSTRACTDiabetic peripheral neuropathy is one of the most prevalent complications of diabetes mellitus. It is the most common type of neuropathy characterized by decreased sensory functions in the lower extremities and substantial neuropathic pain. Based on clinical characterization, it is classified into symmetric and asymmetric neuropathy. The pathological changes and neuronal function impairment during diabetes are associated with various pathways, including polyol pathway activation, advanced glycation end-products formation, oxidative stress, protein kinase C activation, poly ADP-ribose polymerase, and hexosamine pathways. Demyelination, axonal atrophy, nerve fibre loss, reduced regeneration, and loss of neurovascular interactions are hallmarks. Although some symptomatic and supportive therapies, such as tricyclic agents, antiarrhythmics, opioid analgesics, incretin, aldose reductase, and protein kinase C inhibitors, are in practice, the outcome is not promising. To fill this gap, natural product-based therapy can prove prodigious as an effective alternative. This review aims to comprehend the available literature on the role of various biological molecules in ameliorating diabetic peripheral neuropathy. These molecules play a key role in reducing oxidative-nitrosative stress, aldose reductase activity, and neuronal apoptosis. They control glucose and HbA1c% levels and improve nerve conduction velocity, axonal regeneration, and antioxidant species (catalase, superoxide dismutase, malondialdehyde). They are known for their attenuating thermal and mechanical hyperalgesia and tactile allodynia. Therefore, there is a need to evaluate these molecules at the pre-clinical and clinical levels for efficacy. Hence, natural molecules may act as promising players against diabetic peripheral neuropathy and are a ray of hope for suffering individuals.

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.