Clinical Medical School, Dali University, Dali, China.
Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, Jiangsu Province, China.
Brain Res. 2024 May 15;1831:148829. doi: 10.1016/j.brainres.2024.148829. Epub 2024 Feb 27.
To investigate the expression of the precursor of brain-derived neurotrophic factor (proBDNF) and its high-affinity receptor p75NTR in neurons of emotion-related brain areas (prefrontal cortex, hippocampus, and amygdala) in rats with post-stroke depression (PSD), and to explore the expression levels of proBDNF and p75NTR in neurons of emotion-related brain areas by injecting tissue plasminogen activator (t-PA) into the lateral ventricle of PSD rats, this significantly improved the stress-induced depression-like behavior,thus further validating the above results.
Rats were randomly divided into four groups: a normal control group (n = 8), a depression group (n = 8), a stroke group (n = 8), and a PSD group (n = 8). The rat model of stroke was established by thread embolism, and the PSD animal model was induced by chronic unpredictable mild stress (CUMS) and solitary feeding. Behavioral tests were conducted, including weight measurement, open field tests, and sucrose preference tests. Immunofluorescence double labeling was used to detect the expression of proBDNF and p75NTR in neurons of emotion-related brain regions in the PSD rat model. Four weeks after CUMS treatment, the PSD group was selected. Rats were infused with t-PA (3 μg dissolved in 6 μL saline, Boehringer Ingelheim), proBDNF (3 μg dissolved in 6 μL saline, Abcam), or equal-volume NS once per day for 7 consecutive days using the syringe pump connecting to injection needles. After 7 days of continuous administration, animal behavior was assessed through scoring, and the expression of proBDNF and p75NTR in the emotion-related brain regions of the PSD rat model was detected using immunofluorescence double labeling.
Compared with the normal control group and the stroke group, the body weight, sucrose water consumption, and vertical movement distance in the PSD group were significantly lower (P < 0.05). In contrast, when compared with the proBDNF injection group and saline injection group, the weight, sucrose water consumption, field horizontal movement, and vertical movement distance of the t-PA injection group significantly increased after PSD lateral ventricle intubation.Double immunofluorescence revealed a higher neuronal expression of proBDNF as well as p75NTR in the prefrontal cortex and hippocampus of PSD rats compared to control animals (P < 0.05). In the amygdala, the expression levels of proBDNF and P75NTR were significantly reduced in the PSD group compared to the control group (P < 0.05). The results of the expression levels of proBDNF and P75NTR in the emotion-related brain regions of PSD rats injected with t-PA showed that proBDNF and P75NTR was significantly reduced in the prefrontal cortex, hippocampus, and amygdala of PSD rats compared to those of the NS and proBDNF groups (P < 0.05).
The increased expression of the brain-derived neurotrophic factor precursor proBDNF and its receptor p75NTR in neurons of emotion-related brain regions may play an important role in the pathogenesis of PSD.t-PA reduced the expression of proBDNF and its receptor p75NTR in neurons emotion-related brain regions and significantly improved the stress-induced depression-like behavior. Therefore, it is reasonable to assume that exogenous injection of t-PA may alleviate the depressive symptoms of PSD patients.Reducing the expression of proBDNF by injecting t-PA may provide a novel therapeutic approach for the treatment of stress-related mood disorders.
研究脑源性神经营养因子（proBDNF）前体及其高亲和力受体 p75NTR 在卒中后抑郁（PSD）大鼠情绪相关脑区（前额叶皮层、海马和杏仁核）神经元中的表达，并通过向 PSD 大鼠侧脑室注射组织型纤溶酶原激活物（t-PA）来探讨 proBDNF 和 p75NTR 在情绪相关脑区神经元中的表达水平，从而显著改善应激诱导的抑郁样行为，进一步验证上述结果。
将大鼠随机分为四组：正常对照组（n=8）、抑郁组（n=8）、卒中组（n=8）和 PSD 组（n=8）。采用线栓法建立大鼠卒中模型，采用慢性不可预知性轻度应激（CUMS）和独居饲养诱导 PSD 动物模型。进行体重测量、旷场试验和蔗糖偏好试验等行为学测试。采用免疫荧光双重标记法检测 PSD 大鼠模型情绪相关脑区神经元中 proBDNF 和 p75NTR 的表达。CUMS 处理 4 周后，选择 PSD 组，采用微量注射泵连接注射针每日向大鼠侧脑室注射 t-PA（3μg 溶解于 6μL 生理盐水中，Boehringer Ingelheim）、proBDNF（3μg 溶解于 6μL 生理盐水中，Abcam）或等量 NS，连续 7 天。连续给药 7 天后，通过评分评估动物行为，采用免疫荧光双重标记法检测 PSD 大鼠模型情绪相关脑区 proBDNF 和 p75NTR 的表达。
与正常对照组和卒中组相比，PSD 组大鼠体重、蔗糖水摄入量和垂直运动距离明显降低（P<0.05）。与 proBDNF 注射组和生理盐水注射组相比，PSD 侧脑室插管后 t-PA 注射组大鼠体重、蔗糖水摄入量、场水平运动和垂直运动距离明显增加。双免疫荧光显示 PSD 大鼠前额叶皮层和海马神经元中 proBDNF 以及 p75NTR 的表达水平明显高于对照组（P<0.05）。在杏仁核中，PSD 组 proBDNF 和 P75NTR 的表达水平明显低于对照组（P<0.05）。PSD 大鼠注射 t-PA 后情绪相关脑区 proBDNF 和 P75NTR 的表达水平显示，与 NS 和 proBDNF 组相比，PSD 大鼠前额叶皮层、海马和杏仁核中 proBDNF 和 P75NTR 的表达水平明显降低（P<0.05）。
情绪相关脑区神经元中脑源性神经营养因子前体 proBDNF 及其受体 p75NTR 的表达增加可能在 PSD 的发病机制中起重要作用。t-PA 降低了 PSD 大鼠情绪相关脑区神经元中 proBDNF 和其受体 p75NTR 的表达，并显著改善了应激诱导的抑郁样行为。因此，推测外源性注射 t-PA 可能减轻 PSD 患者的抑郁症状。通过注射 t-PA 降低 proBDNF 的表达可能为应激相关情绪障碍的治疗提供一种新的治疗方法。
