Hypoxic-ischemic encephalopathy (HIE) results in permanent damage of central nervous system that may lead to 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 paly) and mental retardation.It was shown recently that the group II metabotropic glutamate receptors (mGluR2/3) activation before or after ischemic insult results in neuroprotection but the exact mechanism of this effects is not clear. Neonatal H-I in 7-day-old rats was used as an experimental model of british asphyxia. Rats were injected intra peritoneally with mGluR2 (LY 379268) 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. Additionally, the activity of pro-apoptotic enzymes caspase-3 and caspase-9 was measured. The expression of tropphic factors GDNF BDNF, TGF-beta was also measured. Therefore, assuming that the activation of group II mGluRs before H-I may prec=vent ischemic damage and have a neuroprotective effects, we decided to invetigate more closely the molecular mechanism(s) of this effect. The aim of the research was to : 1. determine neuroprotective effects of LY379268 in neonatal rat H-I model, 2. determine the therapeutic window for LY379268 effect, 3. examine the effect of LY 379268 on parameters of oxidative stress, which can be one of the potential factors of neuroprotective action of mGluR2/3 in HI model, 4. determine the effect of LY379268 on apoptotic processes and expression of neurotrophic factors. The main conclusion arising from the results presented in this manuscript is the confirmation that in observed after H-I neuroprotection evoked by LY379268 application, the leading role plays direct effect LY379268 on metabotropic glutamate receptors group II and inhibition of glutamate release that results in decrease of both excitotoxicity and neurodegeneration.
Aug 22, 2019
Feb 8, 2019
Skowrońska, Katarzyna Albrecht, Jan ( Promotor)
Krupska, Olga Zabłocka, Barbara (Promotor)
Lazarewicz, Jerzy Salińska, Elżbieta
Klatzo, Igor Mossakowski, Mirosław Jan (1929 - 2001) Myers, Ronald E. i in.
Mossakowski, Mirosław Jan (1929 - 2001) Long, D. M. Myers, Ronald E. Rodriguez de Curet, H. Klatzo, Igor