Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review

Abstract

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide. While the application of therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this lone treatment option is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE. Here, we present evidence of the neuroprotective effects of targeting Src kinase in preclinical models of HIE.

Methods: We performed a comprehensive literature search using the National Library of Medicine's MEDLINE database to compile studies examining the impact of Src kinase regulation on neurodevelopment in animal models. Each eligible study was assessed for bias.

Results: Twenty studies met the inclusion criteria, and most studies had an intermediate risk for bias. Together, these studies showed that targeting Src kinase resulted in a neuroprotective effect as assessed by neuropathology, enzymatic activity, and neurobehavioral outcomes.

Conclusion: Src kinase is an effective neuroprotective target in the setting of acute hypoxic injury. Src kinase inhibition triggers multiple signaling pathways of the sub-membranous focal adhesions and the nucleus, resulting in modulation of calcium signaling and prevention of cell death. Despite the significant heterogeneity of the research studies that we examined, the available evidence can serve as proof-of-concept for further studies on this promising therapeutic strategy.

Keywords: Src; hypoxia; hypoxic-ischemic encephalopathy (HIE); neonatal brain; neuroprotection.

Figure 1

Flow diagram of the literature search. Modified from the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) and modified to accurately depict the literature research (Moher et al., 2009).

Figure 2

The proposed mechanism of the apoptotic pathway in a developing neuron. During global ischemia, evidence suggests that the three major mechanisms of neuronal cell death (excitoxicity, generation of free radicals and inflammation) are mediated through the phosphorylation of regulatory sites by Src kinases. Failure of the oxidative phosphorylation gives rise to intracellular Ca²⁺ which triggers ecotoxicity and potentiates calcium-dependent apoptotic pathways. Calcium contributes to the generation of free radicals through NO and nNOS and leads to transcription of factors that induces leakage of apoptotic proteins from mitochondria. The inflammation and the extrinsic apoptotic pathway are mediated through TNF and different types of caspases. Created with BioRender.com.