Effect of Advillin Knockout on Diabetic Neuropathy Induced by Multiple Low Doses of Streptozotocin

Abstract

Advillin is an actin-binding protein involved in regulating the organization of actin filaments and the dynamics of axonal growth cones. In mice, advillin is exclusively expressed in somatosensory neurons, ubiquitously expressed in all neuron subtypes during neonatal ages and particularly enriched in isolectin B4-positive (IB4+) non-peptidergic neurons in adulthood. We previously showed that advillin plays a key role in axon regeneration of somatosensory neurons during peripheral neuropathy. Mice lacking advillin lost the ability to recover from neuropathic pain induced by oxaliplatin, chronic compression of the sciatic nerve, and experimental autoimmune encephalitis. However, the role of advillin in painful diabetic neuropathy remains unknown. Diabetic neuropathy, a prevalent complication of types 1 and 2 diabetes mellitus, poses significant treatment challenges because of the limited efficacy and adverse side effects of current analgesics. Here we probed the effect of advillin knockout on neuropathic pain in a diabetic mouse model induced by multiple low doses of streptozotocin (STZ). STZ-induced cold allodynia was resolved in 8 weeks in wild-type (Avil+/+ ) mice but could last more than 30 weeks in advillin-knockout (Avil−/− ) mice. Additionally, Avi−/− but not Avil+/+ mice showed STZ-induced mechanical hypersensitivity of muscle. Consistent with the prolonged and/or worsened STZ-induced neuropathic pain, second-line coping responses to pain stimuli were greater in Avil−/− than Avil+/+ mice. On analyzing intraepidermal nerve density, STZ induced large axon degeneration in the hind paws but with distinct patterns between Avil+/+ and Avil−/− mice. We next probed whether advillin knockout could disturb capsaicin-induced axon regeneration ex vivo because capsaicin is clinically used to treat painful diabetic neuropathy by promoting axon regeneration. In a primary culture of dorsal root ganglion cells, 10-min capsaicin treatment selectively promoted neurite outgrowth of IB4+ neurons in Avil+/+ but not Avil−/− groups, which suggests that capsaicin could reprogram the intrinsic axonal regeneration by modulating the advillin-mediated actin dynamics. In conclusion, advillin knockout prolonged STZ-induced neuropathic pain in mice, which may be associated with the impaired intrinsic capacity of advillin-dependent IB4+ axon regeneration.