Investigation of the effects of humanin on pain threshold, oxidative stress and inflammatory cytokines in neuropatic behavioral pain models

It is known that neuropathic pain may develop due to sciatica, diabetes and the use of chemotherapeutic agents, and studies have shown that mitochondrial dysfunction, increase in reactive oxygen species (ROS) and inflammatory cytokines may play a role in the pathophysiology of painful neuropathies that develop due to these. However, the effect of humanin, a mitochondrial-derived peptide, on neuropathic pain is unknown. The main purpose of this thesis study was to examine the effect of humanin on pain behavior in mice models with 3 different types of neuropathic pain: metabolic (streptozotocin/STZ), toxic (oxaliplatin/OXA) and traumatic (sciatic nerve chronic constriction injury/SCI). Another aim of this thesis study was to examine whether humanin has an effect on oxidative damage and inflammatory cytokine levels, which play a role in the pathophysiology of neuropathic pain. In addition, it was investigated whether the effect of humanin in the STZ-induced neuropathic pain model was mediated by the endogenous opioid system. In this thesis study, mice with neuropathic pain of 3 different etiologies were administered humanin (4 mg/kg) for 15 days and pain threshold values were measured sequentially with hot plate, cold plate and Von Frey tests at one-day intervals. These measurements were performed at 30-minute intervals for 240 minutes. Following humanin treatments, animals were decapitated and serum serum total antioxidant (TAS), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), malondialdehyde (MDA), nicotinamide adenine dinucleotide phosphate (NADPH), total oxidant (TOS), interleukin -1β (IL-1β), interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were analyzed by enzyme-linked immunosorbent assay (ELISA). In 3 different pain behavior tests performed in animals with neuropathic pain caused by STZ, OXA and SCI, it was determined that humanin increased the pain threshold statistically for 15 days (P<0.05). At the same time, it was determined that while humanin increased antioxidant enzyme levels (TAS, SOD, CAT, GSH and NADPH) (P<0.01), it decreased oxidant enzyme levels (TOS and MDA) (P<0.01). While humanin decreased the proinflammatory cytokines measured in this study, it increased the anti-inflammatory cytokines (P<0.01). In addition, it was determined that the antihypersensitive effect of humanin in STZ-induced neuropathic pain was mediated by the endogenous opioid system. The results of this thesis study show the therapeutic potential of humanin, a mitochondrial-derived peptide, in neuropathic pain caused by STZ, OXA and SCI, and will also contribute to the understanding of the role of oxidative stress and inflammatory cytokines in this potential effect.