Abstract
1H-MRS technology can be used to non-invasively detect the content of cerebral metabolites, to assess the severity of hypoxic-ischemic (HI) injury, and to predict the recovery of compromised neurological function. However, changes to the cerebral self-regulation process after HI are still unclear. This study investigated the changes in cerebral metabolites and the potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) using 1H-MRS, and finally clarifies the self-regulation of cerebral metabolism and neuroprotection after HI injury. Newborn Yorkshire pigs (28 males, 1.0–1.5 kg) aged 3–5 days were used for the HI model in this study. The pigs were randomly divided into the HI group (n = 24) and the control group (n = 4), then the experimental group was subdivided according to different recovery time after HI into the following groups: 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4). Following the HI timepoints, 1H-MRS scans were performed and processed using LCModel software, and brain tissue was immunohistochemically stained for Nestin and NeuN. Immunofluorescence staining of creatine phosphokinase-BB (CK-BB), N-acetylaspartylglutamate synthetase (NAAGS), glutamate carboxypeptidase II (GCP-II), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthase (GS), and excitatory amino acid carrier 1 (EAAC1) was then performed. The 1H-MRS results showed that cerebral N-acetylaspartylglutamate (NAAG), glutathione (GSH), and creatine (Cr) content reached their peaks at 12–24 h, which was consistent with the recovery time of hippocampal NSPCs and neurons, indicating a potential neuroprotective effect of NAAG, GSH, and Cr after HI injury.
Highlights
Hypoxic-ischemic (HI) injury is one of the major causes of neonatal encephalopathy, mainly causes damage to the cerebral cortex, hippocampus, basal ganglia, and thalamus and can lead to complications such as cerebral palsy, epilepsy, and cognitive impairment (Kurinczuk et al, 2010; Wu et al, 2019)
This study aims to investigate the changes in cerebral metabolites and their potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) by 1H-MRS, and Abbreviations: HI, hypoxic ischemia; ATP, adenosine triphosphate; PCr, phosphocreatine; oxidativeCerebral Metabolism and Neuroprotection phosphorylation (OXPHOS), oxidative phosphorylation; ADP, adenosine diphosphate; CK, creatine kinase; Cr, creatine; ROS, reactive oxygen species; Glu, glutamic acid; Gln, glutamine; NAAG, N-acetylaspartylglutamate; NAA, N-acetylaspartate; GCP-II, glutamate carboxypeptidase II; EAAC1, excitatory amino acid carrier 1; mGluR3, metabotropic glutamate receptor type 3; GSH, glutathione; MAS, malate-aspartate shuttle; Asp, aspartic acids; CK-BB, creatine phosphokinase-BB; N-acetylaspartylglutamate synthetase (NAAGS), NAAG synthetase;GS, glutathione synthase; GCLC, glutamate-cysteine ligase catalytic subunit; γ-GC, γ-glutamylcysteine; PPP, pentose phosphate pathway
Asp content was significantly reduced at 0–2 h (P = 0.032; LSD test), and increased at 48–72 h compared with the 12–24 h group (P = 0.047; LSD test)
Summary
Hypoxic-ischemic (HI) injury is one of the major causes of neonatal encephalopathy, mainly causes damage to the cerebral cortex, hippocampus, basal ganglia, and thalamus and can lead to complications such as cerebral palsy, epilepsy, and cognitive impairment (Kurinczuk et al, 2010; Wu et al, 2019). Cerebral Metabolism and Neuroprotection phosphorylation (OXPHOS), impaired energy metabolism, accumulated glutamic acid (Glu) in the synaptic cleft, overactivated glutamate receptors, overloaded intracellular calcium, and accumulated reactive oxygen species (ROS) after HI all cause damage to neural cells (Pregnolato et al, 2019; Qin et al, 2019). As the important antioxidant in the body, glutathione (GSH) can protect cells from oxidative damage by removing ROS in a reaction catalyzed by glutathione peroxidase (Thorwald et al, 2019). Another process, mediated by the malate-aspartate shuttle (MAS), includes amino acid conversion but is closely related to energy metabolism. After shuttling into the mitochondria, malic acid and Glu are converted into aspartic acid (Asp) and α-ketoglutarate, which is tightly coupled with the NAD+/NADH electron transport chain in neurons and further provides cellular energy (Xu et al, 2020)
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