Elevated miR-29a Contributes to Axonal Outgrowth and Neurological Recovery After Intracerebral Hemorrhage via Targeting
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ORIGINAL RESEARCH
Elevated miR‑29a Contributes to Axonal Outgrowth and Neurological Recovery After Intracerebral Hemorrhage via Targeting PTEN/PI3K/Akt Pathway Manman Zhao1 · Junling Gao2,3 · Yanan Zhang3 · Xiaohua Jiang2,3 · Yanxia Tian3 · Xuecheng Zheng1 · Kaijie Wang4 · Jianzhong Cui1,4 Received: 12 April 2020 / Accepted: 14 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 miR-29a · Intracerebral hemorrhage · Axonal outgrowth · PTEN · Neurological function
Introduction
* Jianzhong Cui [email protected] 1
Department of Surgery, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang 050017, Hebei, China
2
Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research On Chronic Diseases, Tangshan 063000, Hebei, China
3
Department of Histology and Embryology, North China University of Science and Technology, Tangshan 063000, Hebei, China
4
Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan 063000, Hebei, China
Spontaneous intracerebral hemorrhage (ICH) is the most lethal subtype of stroke with high mortality and disability, accounting for 10–15% of all strokes in western countries and 20–30% of strokes in Asia (Tao et al. 2017). Notably, most survivors are left with moderate or even
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