Neonatal asphyxia as an inflammatory disease: Reactive oxygen species and cytokines

Abstract

Neonatologists resuscitate asphyxiated neonates by every available means, including positive ventilation, oxygen therapy, and drugs. Asphyxiated neonates sometimes present symptoms that mimic those of inflammation, such as fever and edema. The main pathophysiology of the asphyxia is inflammation caused by hypoxic-ischemic reperfusion. At birth or in the perinatal period, neonates may suffer several, hypoxic insults, which can activate inflammatory cells and inflammatory mediator production leading to the release of larger quantities of reactive oxygen species (ROS). This in turn triggers the production of oxygen stress-induced high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular patterns (DAMPs) protein bound to toll-like receptor (TLR) -4, which activates nuclear factor-kappa B (NF-κB), resulting in the production of excess inflammatory mediators. ROS and inflammatory mediators are produced not only in activated inflammatory cells but also in non-immune cells, such as endothelial cells. Hypothermia inhibits pro-inflammatory mediators. A combination therapy of hypothermia and medications, such as erythropoietin and melatonin, is attracting attention now. These medications have both anti-oxidant and anti-inflammatory effects. As the inflammatory response and oxidative stress play a critical role in the pathophysiology of neonatal asphyxia, these drugs may contribute to improving patient outcomes.

Effects of Cannabidiol, Hypothermia, and Their Combination in Newborn Rats with Hypoxic-Ischemic Encephalopathy

“…Thus, hypothermia induces beneficial metabolic changes for the maintenance of neuronal ATP, favoring brain homeostasis ( Kuffler, 2010 ). Although the mechanism of action of hypothermia is still largely unknown, it is believed to involve multiple targets and to participate in the suppression of different inflammatory pathways, inhibiting proinflammatory cytokines, and promoting anti-inflammatory cytokines ( Okazaki et al, 2023 ), and would reduce excitotoxicity ( Drury et al, 2014 ) and programmed cell death associated with the caspase family ( Shamas-Din et al, 2011 ). CBD possesses affinity and functional activity at many molecular targets ( Ibeas Bih et al, 2015 ), and thus the mechanisms by which CBD exerts its neuroprotective effects after neuronal damage are not fully understood.…”

Reactive Gliosis in Neonatal Disorders: Friend or Foe for Neuroregeneration?

“…These factors were, however, shown to be directly activated by signaling factors engaged in immune responses, such as pro-inflammatory cytokines and bacterial lipopolysaccharides [83][84][85], predominantly via the canonical NF-κB signaling pathway (nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway) [86]. Neuroinflammation and the upregulated production of cytokines are evoked in neonatal brains not only due to infections but also as a result of perinatal asphyxia [87].…”

Pathomechanisms of Prenatally Programmed Adult Diseases

“…Inflammatory responses to OS can be achieved via the activation of the TLR-4 mediated NF-κB and IL-6/STAT 3 signaling pathways. Hypoxiainduced IL-1β and HIF-1 may also contribute to these mechanisms [110].…”