Abstract
Neonatal hypoxic ischemic encephalopathy (HIE) due to birth asphyxia is common and causes severe neurological deficits, without any effective therapies currently available. Neuronal death is an important driving factors of neurological disorders after HIE, but the regulatory mechanisms are still uncertain. Long non-coding RNA (lncRNA) or ceRNA network act as a significant regulator in neuroregeneration and neuronal apoptosis, thus owning a great potential as therapeutic targets in HIE. Here, we found a new lncRNA, is the most functional in targeting the Igfbp3 gene in HIE, which enriched in the cell growth and cell apoptosis processes. In addition, luciferase reporter assay showed competitive regulatory binding sites to the target gene Igfbp3 between TCONS00044054 (Vi4) and miR-185-5p. The change in blood miR-185-5p and Igfbp3 expression is further confirmed in patients with brain ischemia. Moreover, Vi4 overexpression and miR-185-5p knock-out promote the neuron survival and neurite growth, and suppress the cell apoptosis, then further improve the motor and cognitive deficits in rats with HIE, while Igfbp3 interfering got the opposite results. Together, Vi4-miR-185-5p-Igfbp3 regulatory network plays an important role in neuron survival and cell apoptosis and further promote the neuro-functional recovery from HIE, therefore is a likely a drug target for HIE therapy.
Highlights
Hypoxic ischemic encephalopathy (HIE) is an important cause of death and disability in neonates and typically results in serious long-term sequelae including behavioral and cognitive dysfunction, learning difficulties, cerebral palsy and epilepsy (Busl and Greer, 2010; Shankaran et al, 2012; Yang and Kuan, 2015)
We reported that a novel Long non-coding RNAs (lncRNA) (Vi4) as upregulated in the brain of HIE rats and in cortical neurons under OGD conditions, promoted neurite growth and reduces cell apoptosis of cortical and hippocampal neurons after HI
Through conjoint analysis of bioinformatics prediction and PCR verification, we found that Insulin-like growth factorbinding protein 3 (Igfbp3) was closely correlated with Vi4 in both regulatory sites and function
Summary
Hypoxic ischemic encephalopathy (HIE) is an important cause of death and disability in neonates and typically results in serious long-term sequelae including behavioral and cognitive dysfunction, learning difficulties, cerebral palsy and epilepsy (Busl and Greer, 2010; Shankaran et al, 2012; Yang and Kuan, 2015). Long non-coding RNAs (lncRNA) are currently thought to be crucial regulators of genomic imprinting, chromatin remodeling, transcription, and cell cycles, and their expression is spatially and temporally restricted to cell types and stages of development (Clark and Blackshaw, 2014). Their function and mechanism of action are not fully clear, perturbations in lncRNA expression have been implicated in many diseases, including Alzheimer’s disease, heart pathology, and multiple forms of cancer (Clark and Blackshaw, 2014). Advances in molecular biology technology have led to a more in-depth understanding of HIE pathogenesis
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