Spontaneous intracerebral hemorrhage (ICH) is a clinical challenge with high disability and lacks an effective treatment. miR-29a strongly expressed in the brain has been implicated in various neurological disorders. In this study, we investigated the biological roles of miR-29a in axonal outgrowth and neurological outcomes after ICH and relevant molecular mechanism. The rat model of ICH was established by injection of autologous whole blood into the right basal ganglia. First, a significant decrease in miR-29a level was found in perihematomal brain tissues and cerebrospinal fluid (CSF) after ICH in vivo and hemin-treated neurons in vitro. Further study documented that lentivirus-mediated miR-29a overexpression could remarkably attenuate hemorrhagic brain injury, promoted regenerative outgrowth of injured axons and improved neurobehavioral and cognitive impairments after ICH in rats. In addition, we also identified that overexpression of miR-29a obviously alleviated neuronal damage and mitochondrial dysfunctions, and facilitated neurite outgrowth in cultured neurons exposed to hemin in vitro. Furthermore, luciferase reporter assay showed that miR-29a directly targeted the 3′-UTR region of phosphatase and tensin homolog (PTEN) mRNA and negatively regulated its expression. More importantly, pharmacological inhibition of PTEN has similar neuroprotective effects as miR-29a overexpression involving activation of the PI3K/Akt pathway after hemorrhagic stroke. Collectively, these results suggested that elevated miR-29a could contribute to axonal outgrowth and neurological recovery through targeting PTEN/PI3K/Akt pathway after ICH, thereby providing a potential therapeutic target for patients with ICH.

自发性脑出血 (ICH) 是一种临床挑战，具有高度残疾，缺乏有效的治疗方法。在大脑中强烈表达的 miR-29a 与各种神经系统疾病有关。在这项研究中，我们研究了 miR-29a 在 ICH 后轴突生长和神经系统结果中的生物学作用以及相关的分子机制。通过将自体全血注入右侧基底节建立脑出血大鼠模型。首先，在体内 ICH 和体外用血红素处理的神经元后，发现血肿周围脑组织和脑脊液 (CSF) 中 miR-29a 水平显着降低。进一步的研究表明，慢病毒介导的 miR-29a 过表达可以显着减轻出血性脑损伤，促进受损轴突的再生生长并改善大鼠 ICH 后的神经行为和认知障碍。此外，我们还发现，在体外暴露于血红素的培养神经元中，miR-29a 的过表达明显减轻了神经元损伤和线粒体功能障碍，并促进了神经突的生长。此外，荧光素酶报告基因检测显示 miR-29a 直接靶向磷酸酶和张力蛋白同源物 (PTEN) mRNA 的 3'-UTR 区域并负调控其表达。更重要的是，PTEN 的药理学抑制具有与 miR-29a 过表达相似的神经保护作用，包括在出血性中风后激活 PI3K/Akt 通路。集体，