Abstract
Hypoxic-ischemic (HI) injury is one of the initial factors contributing to neonatal brain injury. Src family kinases (SFKs) are considered to act as molecular hubs for N-methyl-d-aspartate receptor (NMDAR) regulation and participate in the HI injury process. The objectives of this study were to evaluate the levels of phospho-Src (p-Src), the relationship between NMDARs and SFKs, and the effects of SFK inhibition on an immature rat HI brain injury model. The model was induced in 3-day-old Sprague–Dawley rats using the Rice-Vannucci model operation. The level of p-Src was evaluated using Western blotting. The association of NMDARs with SFKs was detected using Western blotting and coimmunoprecipitation. After intraperitoneal injection of 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2), an SFK-selective inhibitor, neuropathological changes were observed by performing H&E and immunofluorescence staining, and the neurological functions were assessed using the following behavioral tests: modified neurological severity score, open field test, and Morris water maze test. The levels of p-Src first decreased at 0 h after injury, increased at 2 h after injury, and continuously decreased from 6 h to 3 days. Along with the increased p-Src levels observed at 2 h after injury, the phosphorylation of NMDAR subunit NR2B at tyrosine 1472 was increased. Following the administration of PP2, the increased p-Src and NMDAR-2B levels detected at 2 h after injury were decreased, and tissue injury and myelin basic protein expression were improved at 7 days after injury. The PP2 intervention improved the performance of injured rats on behavioral tests. In conclusion, we determined the patterns of p-Src expression after HI brain injury in immature rats and showed a relationship with the activated NMDA receptor. The inhibition of p-Src ameliorates neuropathological changes and damages neurological functions induced by HI injury.
Highlights
A high risk of brain injuries has been observed in preterm survivors, resulting in cognitive, attentional, and motor deficits in 25–50% of patients (Back, 2017)
We identified the pattern of activated Src family kinases (SFKs) expression in an immature rat HI brain injury model and analyzed the relationship of SFKs with N-methyl-d-aspartate receptor (NMDAR)
We discovered changes in the phosphorylation of SFKs over time after injury, the relationship between SFKs and NMDARs, and the neuroprotective effects of PP2 administration
Summary
A high risk of brain injuries has been observed in preterm survivors, resulting in cognitive, attentional, and motor deficits in 25–50% of patients (Back, 2017). The etiology of preterm brain injury is complex and includes the immature brain, the external insults, and the vulnerability of principal components, such as preoligodendrocytes (pre-OLs), cerebral cortex, subplate neurons, thalamus, and basal ganglia (Volpe, 2019). The injured brain shows a decrease in the number of subplate neuronal axons in the cortex and alterations in the maturation and myelination of regenerative OLs, decreasing the number of ensheathed axons (Volpe, 2009, 2019). Brain-derived neurotrophic factor (BDNF) modulates the myelination of OLs by regulating the phosphorylation of SFKs through extracellular signal-regulated kinase (ERK) and receptors expressed on OLs (Peckham et al, 2016)
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