Zhang Linlin, Zhao Fangshi, Li Yize, Song Zhenhua, Hu Lingyue, Li Yuanjie, Zhang Rui, Yu Yonghao, Wang Guolin, Wang Chunyan
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.
Department of Radiology and Tianjin Key Laboratory of Functional Imaging and Tianjin Institute of Radiology, Department of Medical Imaging, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Redox Biol. 2025 Feb;79:103472. doi: 10.1016/j.redox.2024.103472. Epub 2024 Dec 17.
Chronic itch which is primarily associated with dermatologic, systemic, or metabolic disorders is often refractory to most current antipruritic medications, thus highlighting the need for improved therapies. Oxidative damage is a novel determinant of spinal pruriceptive sensitization and synaptic plasticity. The resolution of oxidative insult by molecular hydrogen has been manifested. Herein, we strikingly report that both hydrogen gas (2 %) inhalation and hydrogen-rich saline (5 mL/kg, intraperitoneal) injection prevent and alleviate persistent dermatitis-induced itch, diabetic itch and cholestatic itch. Hydrogen therapy reverses the decrease of spinal SIRT1 expression and antioxidant enzymes (SOD, GPx and CAT) activity after dermatitis, diabetes and cholestasis. Furthermore, hydrogen reduces spinal ROS generation, oxidation products (MDA, 8-OHdG and 3-NT) accumulation, β-catenin acetylation and dendritic spine density in persistent itch models. Spinal SIRT1 inhibition eliminates antipruritic and antioxidative effects of hydrogen, while SIRT1 agonism attenuates chronic itch phenotype, spinal β-catenin acetylation and mitochondrial damage. β-catenin inhibitors are effective against chronic itch via reducing β-catenin acetylation, blocking ERK phosphorylation and elevating antioxidant enzymes activity. Hydrogen treatment suppressed dermatitis and cholestasis mediated spontaneous excitatory postsynaptic currents in vitro. Additionally, hydrogen impairs cholestasis-induced the enhancement of cerebral functional connectivity between the right primary cingulate cortex and bilateral sensorimotor cortex, as well as bilateral striatum. Taken together, this study uncovers that molecular hydrogen protects against chronic pruritus and spinal pruriceptive sensitization by reducing oxidative damage via up-regulation of SIRT1-dependent β-catenin deacetylation in mice, implying a promising strategy in translational development for itch control.
主要与皮肤、全身或代谢紊乱相关的慢性瘙痒通常对目前大多数止痒药物具有难治性，因此凸显了改进治疗方法的必要性。氧化损伤是脊髓瘙痒感受性致敏和突触可塑性的一个新决定因素。分子氢对氧化损伤的修复作用已经得到证实。在此，我们惊人地报告，吸入氢气（2%）和腹腔注射富氢盐水（5 mL/kg）均可预防和减轻持续性皮炎引起的瘙痒、糖尿病性瘙痒和胆汁淤积性瘙痒。氢疗法可逆转皮炎、糖尿病和胆汁淤积后脊髓SIRT1表达的降低以及抗氧化酶（SOD、GPx和CAT）活性的下降。此外，在持续性瘙痒模型中，氢可减少脊髓ROS的产生、氧化产物（MDA、8-OHdG和3-NT）的积累、β-连环蛋白的乙酰化以及树突棘密度。脊髓SIRT1抑制消除了氢的止痒和抗氧化作用，而SIRT1激动剂则减轻了慢性瘙痒表型、脊髓β-连环蛋白乙酰化和线粒体损伤。β-连环蛋白抑制剂通过减少β-连环蛋白乙酰化、阻断ERK磷酸化和提高抗氧化酶活性来有效对抗慢性瘙痒。氢处理在体外抑制了皮炎和胆汁淤积介导的自发性兴奋性突触后电流。此外，氢削弱了胆汁淤积引起的右侧初级扣带回皮质与双侧感觉运动皮质以及双侧纹状体之间脑功能连接的增强。综上所述，本研究揭示分子氢通过上调SIRT1依赖的β-连环蛋白去乙酰化来减少氧化损伤，从而预防慢性瘙痒和脊髓瘙痒感受性致敏，这意味着在瘙痒控制的转化研究中是一种有前景的策略。
