Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
目的 探讨利拉鲁肽调控核因子E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(GPX4)铁死亡信号对DKD大鼠的保护作用。方法 12只雄性SD大鼠随机分为正常对照(NC)组、DKD组和利拉鲁肽治疗(Lir)组,每组4只。检测各组24 h UAlb、TC、TG、LDL-C、血...目的 探讨利拉鲁肽调控核因子E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(GPX4)铁死亡信号对DKD大鼠的保护作用。方法 12只雄性SD大鼠随机分为正常对照(NC)组、DKD组和利拉鲁肽治疗(Lir)组,每组4只。检测各组24 h UAlb、TC、TG、LDL-C、血肌酐(Scr)、BUN、亚铁离子(Fe^(2+))、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MDA),采用HE、PAS、PASM?Masson染色观察肾脏病理学变化,免疫荧光检测肾组织中活性氧簇(ROS)定位及表达,Western blot法检测Nrf2和GPX4蛋白表达。结果 与NC组比较,DKD组24 h UAlb、Scr、BUN、TC、TG、LDL?C、MDA、ROS、Fe^(2+)升高(P<0.05或P<0.01),GSH-Px及Nrf2、GPX4蛋白表达降低(P<0.01)。与DKD组比较,Lir组24 h UAlb、BUN、TC、TG、LDL-C、MDA、ROS、Fe^(2+)降低(P<0.05或P<0.01),GSH-Px及Nrf2、GPX4蛋白表达升高(P<0.01)。结论 利拉鲁肽可能通过上调Nrf2/GPX4信号通路,抑制铁死亡,发挥DKD保护作用。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
文摘目的 探讨利拉鲁肽调控核因子E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(GPX4)铁死亡信号对DKD大鼠的保护作用。方法 12只雄性SD大鼠随机分为正常对照(NC)组、DKD组和利拉鲁肽治疗(Lir)组,每组4只。检测各组24 h UAlb、TC、TG、LDL-C、血肌酐(Scr)、BUN、亚铁离子(Fe^(2+))、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MDA),采用HE、PAS、PASM?Masson染色观察肾脏病理学变化,免疫荧光检测肾组织中活性氧簇(ROS)定位及表达,Western blot法检测Nrf2和GPX4蛋白表达。结果 与NC组比较,DKD组24 h UAlb、Scr、BUN、TC、TG、LDL?C、MDA、ROS、Fe^(2+)升高(P<0.05或P<0.01),GSH-Px及Nrf2、GPX4蛋白表达降低(P<0.01)。与DKD组比较,Lir组24 h UAlb、BUN、TC、TG、LDL-C、MDA、ROS、Fe^(2+)降低(P<0.05或P<0.01),GSH-Px及Nrf2、GPX4蛋白表达升高(P<0.01)。结论 利拉鲁肽可能通过上调Nrf2/GPX4信号通路,抑制铁死亡,发挥DKD保护作用。
