Clinical Lab, Cangzhou Central Hospital, Cangzhou, China.
Department of Pharmacy, Cangzhou Central Hospital, Cangzhou, China.
Neurosci Lett. 2021 May 1;752:135842. doi: 10.1016/j.neulet.2021.135842. Epub 2021 Mar 22.
Numerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms.
Weight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot.
Compared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI.
Androgen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.
大量文献表明，褪黑素给药与创伤性脑损伤（TBI）后死亡率降低和神经结局改善相关。然而，与褪黑素相关的几种疾病存在显著的性别差异。我们旨在确定雄激素是否导致女性对 TBI 的褪黑素易感性增强，以及潜在的分子机制。
使用重物跌落法建立 TBI 啮齿动物模型。TBI 后，每天通过皮下注射分别给予褪黑素（10mg/kg）和睾酮（1mg/kg）三次，共三天。TBI 后 7 天，使用旷场试验评估运动和探索活动。TBI 后 7 天，通过免疫荧光法评估神经元数量、神经元凋亡以及磷酸化细胞外调节蛋白激酶 1/2（ERK1/2）、c-jun N-末端激酶 1/2（JNK1/2）和 p38 丝裂原活化蛋白激酶（p38MAPK）在神经元中的表达。使用 Western blot 检测额皮质中 caspase-3、Bax 和 Bcl-2 的表达。
与雄性大鼠相比，TBI 暴露的雌性大鼠给予褪黑素后表现出更多的神经保护作用（包括改善运动和探索活动、增加神经元数量和减少神经元凋亡）。此外，睾酮可显著改善 TBI 暴露的雌性大鼠的运动和探索活动、增加神经元数量、减少神经元凋亡、下调 JNK1/2-和 p38MAPK 阳性神经元的磷酸化，但上调 ERK1/2 阳性神经元的磷酸化，并减少额皮质中 cleaved caspase-3、Bax 的表达，但增加 Bcl-2 的表达。
雄激素通过可能与 MAPK 通路调节相关的机制，导致女性在褪黑素补充下对 TBI 的易感性增强。
