1 2 3 4 Plasminogen repairs abnormal pain perception through improving sensory function 5 recovery and regeneration of peripheral small nerve fiber in db/db mice 6 7 Painful diabetic peripheral neuropathy (PDPN) is a devastating complication of 34 diabetes and severely threatens the health of humankind. The plasminogen activator 35 system and plasminogen (Plg) have multiple functional roles in tissue regeneration and36 extracellular matrix remodeling, which suggests that Plg may have a potentially pivotal 37 role in anti-PDPN. In the present study, we explore whether an increased level of 38 circulating Plg has positive effect on repairing abnormal pain perception in diabetic mice 39 model. Our data demonstrated that additional Plg not only helps healing pain allodynia or 40 hyperalgesia on the mice at the age of 8 weeks old in early PDPN, but more important, 41 also has positive effects of regaining normal pain perception from hypoalgesia on the 42 mice at ages of 14-15 or 24-25 weeks in advanced PDPN. Furthermore, our data also 43 reveal a possible mechanism for Plg's contribution to rebuilding normal pain perception 44 among db/db mice by promoting axonal myelination and regeneration of small nerve 45 fiber in peripheral nervous system. Therefore, our data suggest that Plg show promise to 46 become a drug candidate for treating diabetic peripheral neuropathic pain. 47 48 Introduction 49 Painful diabetic peripheral neuropathy (PDPN) is a common complication 50 accompanying long term Diabetes Mellitus (DM), affecting approximately 50% diabetic 51 patients [1]. PDPN has been recently defined as a symmetric, length-dependent 52 sensorimotor polyneuropathy attributable to metabolic and microvascular alterations as a 53 result of chronic hyperglycemia exposure [2]. Though the specific pathogenesis of PDPN 54 in different stages has not been fully clarified, but it is known that there are two stages 55 according to the manifestations, the early PDPN and the advanced PDPN. Such 56 manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon 57 described in early PDPN; 2) thermal hypoalgesia, typically present in advanced PDPN; 3) 58 mechanical hyperalgesia, an equivalent of pain on pressure in early PDPN; 4) mechanical 59 hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in 60 advanced PDPN 5) tactile allodynia, a painful perception of a light touch [3]. 20-30% of 61 patients with PDPN suffer from severe neuropathic pain [4-5], as a leading cause for foot 62 ulceration and amputation and fall related injury. This may result in withdrawal from 63 social events there by affecting the quality of life and considerably increasing the 64 financial burden of treatment [6-8]. 65 Unfortunately, so far, there are no effective FDA approved drugs available for 66 treating PDPN [9-10]. At present, traditional drugs including (1) antiepileptic drugs, such 67 as gabapentin and pregabalin; (2) analgesics and anesthetics; (3) antidepressants and non-68 steroidal anti-inflammatory...
