Neuroprotective effects of metabotropic glutamate receptors group II (mGluR2/3) agonists in an animal model of brith asphyxia
Hypoxic-ischemic encephalopathy (HIE) results in permanent damage of the central nervous system that may result in neonatal death or developmental disorders. 20% – 30% of infants with HIE die in the neonatal period, and 33% – 50% of survivors demonstrate permanent neurodevelopmental abnormalities, such as cerebral palsy and mental retardation. It was shown recently that group II metabotropic glutamate receptor (mGluR2/3) activation before or after ischemic insult results in neuroprotection, but the exact mechanism of this effect is not clear. AIM(S): The aim of present study was to investigate whether mGluR2/3 activation after hypoxia‑ischemia reduces brain damage and if the reduction of the expression of pro-apoptotic factors is one of the mechanisms involved. METHOD(S): We used an animal model of hypoxia‑ischemia (H‑I) on 7‑day old rat pups. Animals were anesthetized and the left common carotid artery was isolated, double-ligated and then cut between the ligatures. After completion of the surgical procedure, the pups were subjected to hypoxia (7.4% oxygen in nitrogen for 75 min at 35˚C). Control pups were sham‑operated (anaesthetized and left c.c.a. dissected, but not ligated). Animals were injected intraperitoneally with specific mGluR2 (LY 379268) and mGluR3 (NAAG) agonists 1 h or 6 h after H‑I (5 mg/kg of body weight). The weight deficit of the ischemic brain hemisphere was measured and expression of Bax, Bcl‑2, and HTR/OMI was examined. Damage in the hippocampal CA1 region was examined by cresyl violet (CV) staining. RESULTS: Our results show that application of mGluR2/3 agonists after H‑I results in neuroprotection. Both applied agonists decreased brain tissue weight loss in ischemic hemisphere at both times of application (from 40% in H‑I to 15% – 20% in treated). Histological examination of the brain tissue showed that both mGluR2/3 agonists applied 1h or 6 h after H‑I decreased the damage of neuronal cells and the disorganization of CA1 region of hippocampus. Both agonist mGluR2/3 applied 1h or 6 h after H‑I were associated with decreased expression of BAX and HTR/OMI and increased expression of Bcl-2 in the ischemic brain hemisphere as compared to H‑I. CONCLUSIONS: The results show that activation of mGluR2 or mGluR3 in a short time after H-I insult triggered neuroprotective mechanisms and reduced apoptotic processes initiated by H‑I in the developing brain. FINANCIAL SUPPORT: This work was performed under the 2016/23/N/NZ7/01942 project.