N-Acetylaspartylglutamate (NAAG) Pretreatment Reduces Hypoxic-Ischemic Brain Damage and Oxidative Stress in Neonatal Rats.

Ewelina Bratek,Elzbieta Salinska,Apolonia Ziembowicz

doi:10.3390/antiox9090877

Ewelina Bratek, Elzbieta Salinska + Show 1 more

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https://doi.org/10.3390/antiox9090877

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Abstract

N-acetylaspartylglutamate (NAAG), the most abundant peptide transmitter in the mammalian nervous system, activates mGluR3 at presynaptic sites, inhibiting the release of glutamate, and acts on mGluR3 on astrocytes, stimulating the release of neuroprotective growth factors (TGF-β). NAAG can also affect N-methyl-d-aspartate (NMDA) receptors in both synaptic and extrasynaptic regions. NAAG reduces neurodegeneration in a neonatal rat model of hypoxia-ischemia (HI), although the exact mechanism is not fully recognized. In the present study, the effect of NAAG application 24 or 1 h before experimental birth asphyxia on oxidative stress markers and the potential mechanisms of neuroprotection on 7-day old rats was investigated. The intraperitoneal application of NAAG at either time point before HI significantly reduced the weight deficit of the ischemic brain hemisphere, radical oxygen species (ROS) content and activity of antioxidant enzymes, and increased the concentration of reduced glutathione (GSH). No additional increase in the TGF-β concentration was observed after NAAG application. The fast metabolism of NAAG and the decrease in TGF-β concentration that resulted from NAAG pretreatment, performed up to 24 h before HI, excluded the involvement mGluR3 in neuroprotection. The observed effect may be explained by the activation of NMDA receptors induced by NAAG pretreatment 24 h before HI. Inhibition of the NAAG effect by memantine supports this conclusion. NAAG preconditioning 1 h before HI results in a mixture of mGluR3 and NMDA receptor activation. Preconditioning with NAAG induces the antioxidative defense system triggered by mild excitotoxicity in neurons. Moreover, this response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning. However, this theory requires further investigation.

Highlights

Perinatal hypoxia is the most common cause of death and damage to the central nervous system in fetuses and newborns
Our investigations showed that HI evoked a significant increase in the transforming growth factor β (TGF-β) concentration in both hemispheres, which is in agreement with reports by other authors [61,66]; we did not observe any additional increase in the TGF-β concentration in HI groups pretreated with NAAG
The present results show that the NAAG pretreatment, applied both 24 h or 1 h before HI, results in a decrease in neuronal death and a significant reduction in radical oxygen species (ROS) production

Summary

Introduction

Perinatal hypoxia is the most common cause of death and damage to the central nervous system in fetuses and newborns. Deprivation of oxygen accompanied by a lack of perfusion to various organs, especially the brain, often leads to symptoms of abnormal neurological function termed neonatal hypoxic-ischemic encephalopathy (neonatal HIE). 2–4 out of every 1000 live newborns are diagnosed with neonatal HIE, and the incidence of neonatal HIE is high in developing countries [1,2,3,4]. The mortality rate of hypoxia-ischemia (HI) in live newborns in these countries is 15%–20% [5]. Conditions such as premature birth enhance vulnerability to HI insults, increasing the incidence of motor and sensory deficits, cognitive impairments and emotional disorders [6,7]. The developing brain has a high metabolic need, and this makes them

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