Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Querétaro, Mexico.
CONAHCYT-Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM-Juriquilla, Querétaro, Mexico.
J Neuroendocrinol. 2024 Oct;36(10):e13415. doi: 10.1111/jne.13415. Epub 2024 May 29.
Ischemic stroke is a significant global health issue, ranking fifth among all causes of death and a leading cause of serious long-term disability. Ischemic stroke leads to severe outcomes, including permanent brain damage and neuronal dysfunction. Therefore, decreasing and preventing neuronal injuries caused by stroke has been the focus of therapeutic research. In recent years, many studies have shown that fluctuations in hormonal levels influence the prognosis of ischemic stroke. Thus, it is relevant to understand the role of hormones in the pathophysiological mechanisms of ischemic stroke for preventing and treating this health issue. Here, we investigate the contribution of the prolactin/vasoinhibin axis, an endocrine system regulating blood vessel growth, immune processes, and neuronal survival, to the pathophysiology of ischemic stroke. Male mice with brain overexpression of prolactin or vasoinhibin by adeno-associated virus (AAV) intracerebroventricular injection or lacking the prolactin receptor (Prlr) were exposed to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. Overexpression of vasoinhibin or the absence of the prolactin receptor led to an increased lesion volume and decreased survival rates in mice following tMCAO, whereas overexpression of prolactin had no effect. In addition, astrocytic distribution in the penumbra was altered, glial fibrillary acidic protein and S100b mRNA expressions were reduced, and interleukin-6 mRNA expression increased in the ischemic hemisphere of mice overexpressing vasoinhibin. Of note, prolactin receptor-null mice (Prlr) showed a marked increase in serum vasoinhibin levels. Furthermore, vasoinhibin decreased astrocyte numbers in mixed hippocampal neuron-glia cultures. These observations suggest that increased vasoinhibin levels may hinder astrocytes' protective reactivity. Overall, this study suggests the involvement of the prolactin/vasoinhibin axis in the pathophysiology of ischemic stroke-induced brain injury and provides insights into the impact of its dysregulation on astrocyte reactivity and lesion size. Understanding these mechanisms could help develop therapeutic interventions in ischemic stroke and other related neurological disorders.
缺血性脑卒中是一个重大的全球健康问题，在所有死因中排名第五，也是严重长期残疾的主要原因。缺血性脑卒中可导致严重后果，包括永久性脑损伤和神经元功能障碍。因此，减少和预防脑卒中引起的神经元损伤一直是治疗研究的重点。近年来，许多研究表明，激素水平的波动会影响缺血性脑卒中的预后。因此，了解激素在缺血性脑卒中病理生理机制中的作用对于预防和治疗这一健康问题至关重要。在这里，我们研究了催乳素/血管抑制素轴在调节血管生长、免疫过程和神经元存活的内分泌系统中对缺血性脑卒中病理生理学的贡献。通过腺相关病毒（AAV）脑室内注射使雄性小鼠脑内过度表达催乳素或血管抑制素，或敲除催乳素受体（Prlr），然后对其进行 45 分钟短暂性大脑中动脉闭塞（tMCAO），再进行 48 小时的再灌注。血管抑制素过度表达或缺乏催乳素受体可导致 tMCAO 后小鼠的病灶体积增大，存活率降低，而催乳素过度表达则没有影响。此外，血管抑制素过度表达的小鼠缺血半球的星型胶质细胞分布发生改变，胶质纤维酸性蛋白和 S100b mRNA 的表达减少，白细胞介素-6 mRNA 的表达增加。值得注意的是，催乳素受体缺失（Prlr）小鼠的血清血管抑制素水平显著升高。此外，血管抑制素可减少混合海马神经元-神经胶质细胞培养物中的星形胶质细胞数量。这些观察结果表明，血管抑制素水平升高可能会阻碍星形胶质细胞的保护反应性。总的来说，这项研究表明催乳素/血管抑制素轴参与了缺血性脑卒中引起的脑损伤的病理生理学过程，并提供了对其失调对星形胶质细胞反应性和病灶大小的影响的深入了解。了解这些机制可能有助于开发缺血性脑卒中及其他相关神经疾病的治疗干预措施。
