Original article Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia

Abstract

A b s t r a c t Introduction: In vitro experiments have demonstrated that preconditioning primary neuronal cultures by temporary application of NMDA receptor antagonists induces long-term tolerance against lethal insults.In the present study we tested whether similar effects also occur in brain submitted to ischemia in vivo and whether the potential benefit outweighs the danger of enhancing the constitutive apoptosis in the developing brain. Material and methods: Memantine in pharmacologically relevant doses of 5 mg/kg or (+)MK-801 (3 mg/kg) was administered i.p. 24, 48, 72 and 96 h before 3-min global forebrain ischemia in adult Mongolian gerbils or prior to hypoxia/ ischemia in 7-day-old rats. Neuronal loss in the hippocampal CA1 in gerbils or weight deficit of the ischemic hemispheres in the rat pups was evaluated after 14 days. Also, the number of apoptotic neurons in the immature rat brain was evaluated. Results: In gerbils only the application of (+)MK-801 24 h before ischemia resulted in significant prevention of the loss of pyramidal neurons. In rat pups administration of (+)MK-801 at all studied times before hypoxia-ischemia

Preconditioning in neuroprotection: From hypoxia to ischemia

“…Slomka et al applied the same protocol to cultured cerebellar cells and observed an increased tolerance as well (Slomka et al, 2014). There have been significant efforts to understand how HPC/IPC confers neuroprotection via its effects on glutamate (Liu et al, 2009) and other neurotransmitters, and new experimental models are testing chemical preconditioning of NMDA receptors to reduce subsequent excitotoxic cell death (Makarewicz et al, 2014; Stetler et al, 2014; Constantino et al, 2015). In a recent study of transient cerebral ischemia and neurons in the gerbil hippocampal CA1 region, kynurenic acid immunoreactivity was maintained or even increased.…”

The Effects of N-Methyl-D-Aspartate Receptor Blockade on Oxidative Status in Heart During Conditioning Maneuvers

“…From these results it can be concluded that activation of NMDAR in nervous tissue may result in protection or damage depending on the localization of NMDAR, as well as on the degree of activation. Several authors indicated the beneficial effects of NMDAR antagonists, primarily MK-801 and memantine, in various models of neuron damage including hypoxia-ischemia and harmful effects of oxygen and glucose deprivation (27,28). Doeppner et al showed that acamprosate, as indirect NMDAR antagonist, exhibited neuroprotective effects if administered 12 hours before stroke, through inhibition of calpain-mediated pro-injurious signaling cascades (29).…”

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

“…It has been demonstrated that the antagonism of NMDARs in the developing brain increases constitutive apoptosis [12,24] and decreases brain weight 2 weeks after a single MK-801 injection [21]. Moreover, NMDAR antagonists interfere with thermoregulation and induce hypothermia in neonatal rats [9].…”