Teixeira-Santos Luísa, Veríssimo Eduardo, Martins Sandra, Sousa Teresa, Albino-Teixeira António, Pinho Dora
Departamento de Biomedicina-Unidade de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal.
Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Universidade do Porto, 4200-319 Porto, Portugal.
Biomedicines. 2023 Jan 31;11(2):416. doi: 10.3390/biomedicines11020416.
NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment with the NOX2-selective inhibitor (NOX2i) GSK2795039 on behavioral responses and spinal neuroinflammation in spared nerve injury (SNI)-induced NP in male and female mice. Mechanical sensitivity was evaluated with the von Frey test, while general well-being and anxiety-like behavior were assessed with burrowing and light/dark box tests. Spinal microglial activation and cytokines IL-1β, IL-6, and IL-10, as well as macrophage colony-stimulating factor (M-CSF) were evaluated by immunofluorescence and multiplex immunoassay, respectively. NOX2i treatment reduced SNI-induced mechanical hypersensitivity and early SNI-induced microglial activation in both sexes. SNI-females, but not males, showed a transient reduction in burrowing activity. NOX2i treatment did not improve their burrowing activity, but tendentially reduced their anxiety-like behavior. NOX2i marginally decreased IL-6 in females, and increased M-CSF in males. Our findings suggest that NOX2-selective inhibition may be a potential therapeutic strategy for NP in both male and female individuals, with particular interest in females due to its apparent favorable impact in anxiety-like behavior.
烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚型2（NOX2）已被认为与神经性疼痛（NP）的病理生理学有关，主要是通过调节神经炎症。由于人们也认识到NP背后的一些神经免疫机制存在性别依赖性，我们旨在评估用NOX2选择性抑制剂（NOX2i）GSK2795039进行早期全身治疗对雄性和雌性小鼠 spared 神经损伤（SNI）诱导的NP行为反应和脊髓神经炎症的影响。用von Frey试验评估机械敏感性，用打洞试验和明暗箱试验评估总体健康状况和焦虑样行为。分别通过免疫荧光和多重免疫测定评估脊髓小胶质细胞活化以及细胞因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和白细胞介素-10（IL-10）以及巨噬细胞集落刺激因子（M-CSF）。NOX2i治疗降低了SNI诱导的两性机械超敏反应和早期SNI诱导的小胶质细胞活化。SNI雌性小鼠而非雄性小鼠的打洞活动出现短暂减少。NOX2i治疗并未改善其打洞活动，但有降低其焦虑样行为的趋势。NOX2i使雌性小鼠的IL-6略有降低，使雄性小鼠的M-CSF增加。我们的研究结果表明，NOX2选择性抑制可能是男性和女性NP的一种潜在治疗策略，由于其对焦虑样行为有明显的有利影响，对女性尤其有意义。
