Elevated miR-29a Contributes to Axonal Outgrowth and Neurological Recovery After Intracerebral Hemorrhage via Targeting PTEN/PI3K/Akt Pathway

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.

Keywords: Axonal outgrowth; Intracerebral hemorrhage; Neurological function; PTEN; miR-29a.