Abstract
BackgroundNeonatal hypoxic-ischemic encephalopathy (HIE) refers to the perinatal asphyxia caused by the cerebral hypoxic-ischemic injury. The current study was aimed at investigating the therapeutic efficacy of Scutellarin (Scu) administration on neurological impairments induced by hypoxic-ischemic injury and exploring the underlying mechanisms.MethodsPrimary cortical neurons were cultured and subjected to oxygen–glucose deprivation (OGD), and then treated with Scu administration. The growth status of neurons was observed by immunofluorescence staining of TUJ1 and TUNEL. Besides, the mRNA level of growth-associated protein 43 (GAP43) in OGD neurons with Scu treatment was detected by quantitative real-time polymerase chain reaction (qRT-PCR). To further verify the role of GAP43 in Scu treatment, GAP43 siRNA and knockout were applied in vitro and in vivo. Moreover, behavioral evaluations were performed to elucidate the function of GAP43 in the Scu-ameliorated long-term neurological impairments caused by HI insult. The underlying biological mechanism of Scu treatment was further elucidated via network pharmacological analysis. Finally, the interactive genes with GAP43 were identified by Gene MANIA and further validated by qRT-PCR.ResultsOur data demonstrated that Scu treatment increased the number of neurons and axon growth, and suppressed cell apoptosis in vitro. And the expression of GAP43 was downregulated after OGD, but reversed by Scu administration. Besides, GAP43 silencing aggravated the Scu-ameliorated neuronal death and axonal damage. Meanwhile, GAP43 knockout enlarged brain infarct area and deteriorated the cognitive and motor dysfunctions of HI rats. Further, network pharmacological analysis revealed the drug targets of Scu participated in such biological processes as neuronal death and regulation of neuronal death, and apoptosis-related pathways. GAP43 exhibited close relationship with PTN, JAK2 and STAT3, and GAP43 silencing upregulated the levels of PTN, JAK2 and STAT3.ConclusionsCollectively, our findings revealed Scu treatment attenuated long-term neurological impairments after HI by suppressing neuronal death and enhancing neurite elongation through GAP43-dependent pathway. The crucial role of Scutellarin in neuroprotection provided a novel possible therapeutic agent for the treatment of neonatal HIE.Graphic abstract
Highlights
Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the perinatal asphyxia caused by the cerebral hypoxic-ischemic injury
Rats were randomly arranged to the four groups for behavioral tests (n = 5/group): HI group, Sham group, HI + SCU + growth-associated protein 43 (GAP43)+/+ group (HI rats received SCU administration), HI + SCU + GAP43−/− group (GAP43-knockout rats were subjected to HI insult and received Scu administration), and the two groups for tetrazolium chloride (TTC) staining (n = 5/group): HI-GAP43+/+ group and HI-GAP43−/− group (GAP43-knockout rats were subjected to HI insult)
The number of neurons in the oxygen–glucose deprivation (OGD) group was significantly reduced in comparison to the normal group and cell number in the Scu 3 μM group was increased compared to the OGD group (Fig. 1d, p < 0.05)
Summary
Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the perinatal asphyxia caused by the cerebral hypoxic-ischemic injury. The current study was aimed at investigating the therapeutic efficacy of Scutellarin (Scu) administration on neurological impairments induced by hypoxic-ischemic injury and exploring the underlying mechanisms. Neonatal hypoxic-ischemic encephalopathy (HIE) has been considered one of the leading causes in neonatal death due to its devastating impact on neonatal brain development [1]. The treatment of HIE prevailingly tends to control cerebral palsy, brain edema, and long-term complications [4], such as fluids therapy [5], antiseizure medication [6], stem cell therapy [7], and hypothermia [8]. Hypothermia has been viewed as the standard care for newborns with HIE, the efficacy for alleviating long-term impairments remains modest and the benefits for infants with severe HIE have been restricted. The underlying mechanisms involved in the process of HIE and more effective therapeutic methods need to be further investigated
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