Abstract
Neonatal hypoxic–ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Neonatal hypoxia–ischemia (HI) injury caused by hypoxia, cerebral blood flow reduction, or short-term cerebral blood flow perfusion interruption in perinatal asphyxia, is a severe disease that usually results in a series of clinical symptoms and signs of central nervous abnormalities
The results of Quantitative reverse transcription polymerase chain reaction (qRT-PCR) in different organs showed that miR-127-3p was and highly expressed in the brain tissue from normal neonatal SD rats, which indicated that miR-127-3p was a miRNA expressed in the central nervous system (Fig. 1C, P < 0.01); it decreased at 12 h, followed by increased at 48 h and 96 h after HI (Fig. 1D, P < 0.01)
Together, our results revealed that the knockdown of miR-127-3p activate autophagy in the cortical neurons by targeting CISD1 overexpression in neonatal rats with neonatal HI injury
Summary
Neonatal hypoxia–ischemia (HI) injury caused by hypoxia, cerebral blood flow reduction, or short-term cerebral blood flow perfusion interruption in perinatal asphyxia, is a severe disease that usually results in a series of clinical symptoms and signs of central nervous abnormalities. Type II programmed cell death caused by autophagy may be involved in regulating neuronal death caused by ischemia[8]. It is of great scientific significance and clinical application value to reveal the regulating mechanism for autophagy in neonatal HI brain injury. MiR-127-3p targeted KIF3B through suppressing cell invasion, migration, and proliferation can inhibit the development of OSCC18, indicating that miR-127-3p is important in several biological processes. The effect of miR-127-3p in neonatal HI injury of brain is largely unknown, and the mechanism of miR-127-3passociated CDGSH iron–sulfur domain-containing protein 1 (CISD1) to regulate autophagic neuron death, is completely unknown, and is needing to be revealed
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