Src Family Kinases Inhibition Ameliorates Hypoxic-Ischemic Brain Injury in Immature Rats

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.

Peripheral Blood Gene Expression at 3 to 24 Hours Correlates with and Predicts 90-Day Outcome Following Human Ischemic Stroke

“…Several of these genes have been implicated in stroke. For example, SKAP1 (Src kinase associated phosphoprotein 1) interacts with Src Family Kinases (SFKs) and stimulates T cell antigen receptors to activate integrins [75, 76]. The T cell-specific hub genes from the 3h WGCNA modules were enriched in pathways such as T Cell-Receptor Signaling and were predicted to be suppressed in subjects with poor 90-day outcomes.…”

Fyn Signaling in Ischemia-Reperfusion Injury: Potential and Therapeutic Implications

“…With the top-to-bottom investigation of Fyn in the field of neurological capacity, Fyn has been affirmed to assume a critical administrative part in neurodevelopment and neuroinflammation. In grown-up rodents, Src or Fyn knockdown can reduce hypoxia-induced neuronal cell death and have neuroprotective effects [ 23 ]. Fyn can likewise be associated with TLR4 to advance cerebral ischemia-incited neuroinflammation [ 24 ].…”

Network pharmacology-based and molecular docking prediction of the active ingredients and mechanism of the herb pair of Huangqi and Taoren for application in ischemic brain injury

“…Ischemic brain injury (IBI) is the main cause of acute mortality and chronic disability in newborns. IBI also is one of the initial factors contributing to neonatal brain injury (Qiu et al 2021). Cerebral ischemia can bring about neuronal necrosis and release in ammatory mediators.…”