The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

Abstract

Hypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to central nervous system (CNS) that may result in neonatal death or manifest later as mental retardation, epilepsy, cerebral palsy, or developmental delay. The primary cause of this condition is systemic hypoxemia and/or reduced cerebral blood flow with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. About 20 to 25% of infants with HIE die in the neonatal period, and 25-30% of survivors are left with permanent neurodevelopmental abnormalities. The mechanisms of hypoxia-ischemia (HI) include activation and/or stimulation of myriad of cascades such as increased excitotoxicity, oxidative stress, N-methyl-D-aspartic acid (NMDA) receptor hyperexcitability, mitochondrial collapse, inflammation, cell swelling, impaired maturation, and loss of trophic support. Different therapeutic modalities have been implicated in managing neonatal HIE, though translation of most of these regimens into clinical practices is still limited. Therapeutic hypothermia, for instance, is the most widely used standard treatment in neonates with HIE as studies have shown that it can inhibit many steps in the excito-oxidative cascade including secondary energy failure, increases in brain lactic acid, glutamate, and nitric oxide concentration. Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein that has been implicated in stimulation of cell survival, proliferation, and function of neutrophil precursors and mature neutrophils. Extensive studies both in vivo and ex vivo have shown the neuroprotective effect of G-CSF in neurodegenerative diseases and neonatal brain damage via inhibition of apoptosis and inflammation. Yet, there are still few experimentation models of neonatal HIE and G-CSF's effectiveness, and extrapolation of adult stroke models is challenging because of the evolving brain. Here, we review current studies and/or researches of G-CSF's crucial role in regulating these cytokines and apoptotic mediators triggered following neonatal brain injury, as well as driving neurogenesis and angiogenesis post-HI insults.

Keywords: Angiogenesis; Apoptosis; Granulocyte-colony stimulating factor; Hypoxia ischemia; Hypoxic-ischemic encephalopathy; Neonatal; Neurogenesis; Pro-inflammatory cytokine.

Fig. 1

Schematic illustration of pathogenic mechanisms of HIE following HI brain injury. Primary energy failure occurs immediately after the hypoxic–ischemic insult. After reperfusion, there is a secondary energy failure, which can extend in duration from 6 to 48 h. Brain injury (tertiary phase) continues to occur months to years after the injury resulting in decreased plasticity and reduced number of neurons. Latent period following resuscitation is ideal for interventions to decrease the impact of secondary energy failure. However, strategies are developed to attenuate tertiary brain damage which will expand the therapeutic window, substantially increasing the beneficial effects of neuroprotection in these infants and hence its impact on long-term outcome. The up arrows represent an increase while the down arrows show a decrease in the corresponding metabolite/process

Fig. 2

Schematic illustration of the potential mechanism of G-CSF action in hypoxia ischemia injury. In the acute phase of cerebral ischemia, G-CSF can protect the brain by inhibiting glutamate release, anti-inflammatory, anti-apoptotic, and inhibit edema formation. In subacute phase, GCSFR can stimulate endogenous neuronal regeneration, mobilization of bone marrow stem cells, driving neuronal regeneration and functional repair, and promote neovascularization (angiogenesis and neurogenesis) during the chronic phase