The activation of group II metabotropic glutamate receptors protects neonatal rat brains from oxidative stress injury after hypoxia-ischemia

Abstract

Birth asphyxia resulting in brain hypoxia-ischemia (H-I) can cause neonatal death or lead to persistent brain damage. Recent investigations have shown that group II metabotropic glutamate receptor (mGluR2/3) activation can provide neuroprotection against H-I but the mechanism of this effect is not clear. The aim of this study was to investigate whether mGluR2/3 agonists applied a short time after H-I reduce brain damage in an experimental model of birth asphyxia, and whether a decrease in oxidative stress plays a role in neuroprotection. Neonatal H-I in 7-day-old rats was used as an experimental model of birth asphyxia. Rats were injected intra peritoneally with mGluR2 (LY 379268) or mGluR3 (NAAG) agonists 1 h or 6 h after H-I (5 mg/kg). The weight deficit of the ischemic brain hemisphere, radical oxygen species (ROS) content levels, antioxidant enzymes activity and the concentrations of reduced glutathione (GSH) were measured. Both agonists reduced weight loss in the ischemic hemisphere and mitigated neuronal degeneration in the CA1 hippocampal region and cerebral cortex. Both agonists reduced the elevated levels of ROS in the ipsilateral hemisphere observed after H-I and prevented an increase in antioxidant enzymes activity in the injured hemisphere restoring them to control levels. A decrease in GSH level was also restored after agonists application. The results show that the activation of mGluR2 and mGluR3 a short time after H-I triggers neuroprotective mechanisms that act through the inhibition of oxidative stress and ROS production. The prevention of ROS production by the inhibition of glutamate release and decrease in its extracellular concentration is likely the main mechanism involved in the observed neuroprotection.

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

“…In the present study, perinatal asphyxia was accompanied by an increase in factors related to apoptosis and oxidative stress, which is in agreement with the results presented by other authors [ 32 – 34 ]. Our study demonstrated that DIM partially downregulated the expression of apoptotic factors, including FAS, CASP-3, and CAPN1, inhibited caspase-9 activity and increased the mRNA expression of anti-apoptotic Bcl2 .…”

“…Before closing, the wound was treated with local anesthetic (lignocainum). After 60 min of recovery, the animals were placed in a humidified chamber (35 °C) and exposed to a hypoxic gas mixture (7.5% oxygen in nitrogen) for 75 min as previously described [16]. After hypoxic treatment, the animals were returned to their cages and housed with their mother at room temperature (22 °C) with a 12:12-h light-dark cycle and ample food and water.…”

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

“…Disrupted glutamatergic neurotransmission, in turn, is a well-recognized factor that contributes to the pathophysiology of neuropsychiatric disorders [41,42]. Studies in animal models revealed that the activation of metabotropic glutamate 2 receptor (mGlu2R) resulted in antipsychotic, memory-enhancing [43], and neuroprotective activity [44], while modulation of NMDA receptors is crucial for neuroplasticity and also influences mood and behavior [40]. Therefore, while developing drugs for dementia-related psychosis in the future, those targeting mGluRs or NMDA receptors can be considered as potential pharmacological targets.…”

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

“…Because of their actions, mGluR2/3 appear to be promising targets for reducing excitotoxicity and neuronal injury. Preclinical studies have demonstrated that the activation of mGluR2 and/or mGluR3 by selective agonists results in neuroprotection in experimental models of ischemia in adult and developing animals [ 38 , 39 , 40 , 41 ]. N -acetylaspartylglutamate (NAAG) is the most abundant and frequently occurring peptide transmitter in the mammalian nervous system.…”

“…The application of NAAG in a short time before or after hypoxia-ischemia protects neurons from excessive NMDA receptor stimulation and reduces brain damage and pro-apoptotic caspase 3 expression [ 39 , 44 ]. We showed in our previous study that the application of NAAG up to 6 h after HI decreases oxidative stress, most likely by reducing excitotoxicity, which may explain its neuroprotective effects [ 38 ]. Based on the papers cited above, most studies have mainly investigated the effect of NAAG application after ischemic insult.…”