The protective effect of heat acclimation from hypoxic damage in the brain involves changes in the expression of glutamate receptors

Abstract

Long-term heat acclimation (34 °C, 30d) alters the physiological responses and the metabolic state of organisms. It also improves ability to cope with hypoxic stress via a cross-tolerance mechanism. Within the brain, the hippocampal and frontal cortex neurons are the most sensitive to hypoxia and cell death is mainly caused by calcium influx via glutamate-gated ion channels, specifically NMDA and AMPA receptors. GluN1 subunit levels of NMDA-R correspond to NMDA-R levels. GluN2B/GluN2A subunit ratio is a qualitative index of channel activity; a higher ratio implies lower calcium permeability. The GluA2 subunit of AMPA-R controls channel permeability by inhibiting calcium penetration. Here, in rats model we (i)used behavioral-assessment tests to evaluate heat acclimation mediated hypoxic (15’ 4.5 ± 0.5% O2) neuroprotection, (ii) measured protein and transcript levels of NMDA-R and AMPA-R subunits before and after hypoxia in the hippocampus and the frontal cortex, to evaluate the role of Ca2+ in neuro-protection/cross-tolerance. Behavioral tests confirmed hypoxic tolerance in long-term (30d) but not in short-term (2d) heat acclimated rats. Hypoxic tolerance in the long-term acclimated phenotype was accompanied by a significant decrease in basal NMDA receptor GluN1 protein and an increase in its mRNA. The long-term acclimated rats also showed post ischemic increases in the GluN2B/GluN2A subunit ratio and GluA2 subunit of the AMPA receptor, supporting the hypothesis that reduced calcium permeability contributes to heat acclimation mediated hypoxia cross-tolerance. Abrupt post ischemic change in GluN2B/GluN2A subunit ratio with no change in NMDA-R subunits transcript levels implies that post-translational processes are inseparable acclimatory cross-tolerance mechanism.

Heat Acclimation, Epigenetics, and Cytoprotection Memory

“…There was a long gap between the 1955 study of Hiestand et al (66) where mice acclimated for 14 days survived anoxia better than the nonacclimated ones and 1993 when data on heat acclimation mediated cross-tolerance began to accumulate (119). We have evidence that heat acclimation induces cross tolerance against several environmental stressors associated with oxygen supply-oxygen demand mismatching such as ischemia/reperfusion, hypoxia (64,77,119,242) hyperoxia (4,42) ionizing radiation (176) TBI (211), and noise induced hearing loss (167).…”

Passive heat therapy protects against endothelial cell hypoxia‐reoxygenation via effects of elevations in temperature and circulating factors

“…) and reduces neuronal damage and cognitive deficits following cerebral hypoxia‐reoxygenation (H/R) (Yacobi et al . ). In humans, we showed that acute hot water immersion protects against reductions in brachial artery endothelial function induced by whole‐arm ischaemia‐reperfusion (Brunt et al .…”

Passive heat therapy for cerebral protection: new ideas of age‐old concepts

“…Yacobi et al . () also demonstrated the importance of glutamate receptors during hypoxic insults, which facilitate neuronal death via calcium penetration following a large glutamate surge. In this study, long term (30 days), but not short term (2 days), heat‐acclimated rats exhibited lower presence of NMDA GluN1 proteins (i.e.…”

“…lower receptor density) and reduced calcium permeability, highlighting different mechanisms by which heat acclimation‐induced hypoxia cross‐tolerance confers neuroprotection (Yacobi et al . ). Importantly, these results translated into improved functional outcomes of behaviour assessment in the 30‐day heat‐acclimated rats following hypoxia, indicating preserved cognitive function (Yacobi et al .…”

“…Importantly, these results translated into improved functional outcomes of behaviour assessment in the 30‐day heat‐acclimated rats following hypoxia, indicating preserved cognitive function (Yacobi et al . ). These studies provide evidence to support the hypothesis that, broadly similarly to Brunt et al .…”