Changes in arginase isoforms in a murine model of neonatal brain hypoxia–ischemia

Abstract

BACKGROUND: Arginases (ARG isoforms, ARG-1/ARG-2) are key regulatory enzymes of inflammation and tissue repair; however, their role after neonatal brain hypoxia (H) and hypoxia-ischemia (HI) remains unknown. METHODS: C57BL/6 mice subjected to the Vannucci procedure on postnatal day (P9) were sacrificed at different timepoints. The degree of brain damage was assessed histologically. ARG spatiotemporal localization was determined via immunohistochemistry. ARG expression was measured by Western blot and activity spectrophotometrically. RESULTS: ARG isoform expression increased during neurodevelopment (P9-P17) in the cortex and hippocampus. This was suppressed with H and HI only in the hippocampus. In the cortex, both isoforms increased with H alone and only ARG-2 increased with HI at 3 days. ARG activity during neurodevelopment remained unchanged, but increased at 1 day with H and not HI. ARG-1 localized with microglia at the injury site as early as 4 h after injury, while ARG-2 localized with neurons. CONCLUSIONS: ARG isoform expression increases with age from P9 to P17, but is suppressed by injury specifically in the hippocampus and not in the cortex. Both levels and activity of ARG isoforms increase with H, while ARG-1 immunolabelling is upregulated in the HI cortex. Evidently, ARG isoforms in the brain differ in spatiotemporal localization, expression, and activity during neurodevelopment and after injury.

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

“…After hypoxia-ischemia (HI) insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in blood-brain barrier (BBB) permeability that allow immune cells to enter and stimulate an inflammatory response ( Moretti et al, 2015 ). Brain resident microglia activate ( Arteaga et al, 2017 ; Li et al, 2011 ; Mike et al, 2020 ) and initiate ROS generation, antigen presentation, phagocytosis, and the production of inflammatory mediators ( Tsuji et al, 2020 ). The neonatal brain is highly susceptible to oxidative stress because of its high concentration of unsaturated fatty acids, high rate of oxygen consumption, availability of redox-active iron ( Halliwell, 1992 ) and because developing endogenous antioxidant mechanisms are rapidly overwhelmed.…”

Early-stage effect of HIBD on neuro-motor function and organic composition of neurovascular units in neonatal rats

“…Experimental evidence also suggests that the expression of Arg-1 increases during normal neurodevelopment of neonatal rats from P9 to P17, and it is primarily localized to microglia. Morphological changes and accumulation of Arg-1-labeled microglia have been observed as early as 4 h after injury (Mike et al, 2021). Previous studies indicate that Arg-1 is primarily associated with the function of "repair-promoting" microglia, and it is commonly used as a marker.…”

Comprehensive Analysis of RNA Expression Profile Identifies Hub miRNA-circRNA Interaction Networks in the Hypoxic Ischemic Encephalopathy

“…Despite the expression of IL-10 was largely studied, the mechanism of IL-10 involving in HIE ignition and progression was still elusive [ 41 ]. Arginases are pivotal modulatory enzymes of inflammation and tissue repair [ 42 ]. At present, it is reported that the expression of ARG-1 in the blood of patients with stroke is heightened, and its level is related to infarct size [ 43 ], implying the involvement of ARG in the mechanisms of post-hypoxic-ischemia.…”