Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China; Institute of Stroke Research, Soochow University, 188 Shizi Street, Suzhou 215006, China.
J Chem Neuroanat. 2023 Oct;132:102318. doi: 10.1016/j.jchemneu.2023.102318. Epub 2023 Jul 22.
Semaphorin 4 C (SEMA4C) and its cognate receptor Plexin B2 are important regulators of axon guidance and are involved in many neurological diseases, in which SEMA4C acts not only as a ligand ("forward" mode) but also as a signaling receptor ("reverse" mode). However, the role of SEMA4C/Plexin B2 in intracerebral hemorrhage (ICH) remains unclear. In this study, ICH in adult male Sprague-Dawley rats was induced by autologous blood injection in the right basal ganglia. In vitro, cultured primary neurons were subjected to OxyHb to imitate ICH injury. Recombinant SEMA4C (rSEMA4C) and overexpressing lentiviruses encoding full-length SEMA4C or secretory SEMA4C (sSEMA4C) were administered to rats by intraventricular injection. First, we found that elevated levels of sSEMA4C in the cerebrospinal fluid (CSF) of clinical patients were associated with poor prognosis. Both SEMA4C and sSEMA4C were increased in brain tissue around the hematoma after ICH in rats. Overexpression of SEMA4C attenuated neuronal apoptosis, neurosis, and neurologic impairment after ICH. However, treatment with rSEMA4C or sSEMA4C overexpression exacerbated neuronal injury. In addition, when treated with SEMA4C overexpression, the forward mode downstream protein RhoA and the reverse mode downstream ID1/3 transcriptional factors of SEMA4C/Plexin B2 signaling were all activated. Nevertheless, when exposed to rSEMA4C or sSEMA4C overexpression, only the forward mode was activated. Thus, sSEMA4C may be a novel molecular biomarker to predict the prognosis of patients with ICH, and the prevention of SEMA4C cleavage is expected to be a promising therapeutic target.
信号素 4C（SEMA4C）及其同源受体 Plexin B2 是轴突导向的重要调节剂，参与许多神经疾病，在这些疾病中，SEMA4C 不仅作为配体（“正向”模式）起作用，而且作为信号受体（“反向”模式）起作用。然而，SEMA4C/Plexin B2 在脑出血（ICH）中的作用尚不清楚。在这项研究中，通过自体血注入右侧基底节诱导成年雄性 Sprague-Dawley 大鼠 ICH。在体外，培养的原代神经元用氧合血红蛋白（OxyHb）处理，模拟 ICH 损伤。通过脑室注射给予大鼠重组 SEMA4C（rSEMA4C）和过表达全长 SEMA4C 或分泌型 SEMA4C（sSEMA4C）的慢病毒。首先，我们发现临床患者脑脊液（CSF）中 sSEMA4C 水平升高与预后不良有关。ICH 后大鼠血肿周围脑组织中 SEMA4C 和 sSEMA4C 均增加。过表达 SEMA4C 可减轻 ICH 后神经元凋亡、神经病变和神经功能障碍。然而，rSEMA4C 或 sSEMA4C 过表达的治疗加重了神经元损伤。此外，当用 SEMA4C 过表达处理时，SEMA4C/Plexin B2 信号的正向模式下游蛋白 RhoA 和反向模式下游 ID1/3 转录因子均被激活。然而，当暴露于 rSEMA4C 或 sSEMA4C 过表达时，只有正向模式被激活。因此，sSEMA4C 可能是预测 ICH 患者预后的新型分子生物标志物，预防 SEMA4C 裂解有望成为有前途的治疗靶点。
