Ischemia-Reperfusion under Hyperthermia Increases Heme Oxygenase-1 in Pyramidal Neurons and Astrocytes with Accelerating Neuronal Loss in Gerbil Hippocampus.

Tae-Kyeong Lee,Ji Hyeon Ahn,Joon Ha Park,Choong-Hyun Lee,Jae-Chul Lee,Dae Won Kim,Jong Dai Kim,Soo Young Choi,Bora Kim,Moo-Ho Won,Hyejin Sim

doi:10.3390/ijms22083963

Abstract

It has been studied that the damage or death of neurons in the hippocampus is different according to hippocampal subregions, cornu ammonis 1–3 (CA1–3), after transient ischemia in the forebrain, showing that pyramidal neurons located in the subfield CA1 (CA1) are most vulnerable to this ischemia. Hyperthermia is a proven risk factor for brain ischemia and can develop more severe and extensive brain damage related with mortality rate. It is well known that heme oxygenase-1 (HO-1) activity and expression is increased by various stimuli in the brain, including hyperthermia. HO-1 can be either protective or deleterious in the central nervous system, and its roles depend on the expression levels of enzymes. In this study, we investigated the effects of hyperthermia during ischemia on HO-1 expression and neuronal damage/death in the hippocampus to examine the relationship between HO-1 and neuronal damage/death following 5-min transient ischemia in the forebrain using gerbils. Gerbils were assigned to four groups: (1) sham-operated gerbils with normothermia (Normo + sham group); (2) ischemia-operated gerbils with normothermia (Normo + ischemia group); (3) sham-operated gerbils with hyperthermia (39.5 ± 0.2 °C) during ischemia (Hyper + sham group); and (4) ischemia-operated gerbils with hyperthermia during ischemia (Hyper + ischemia group). HO-1 expression levels in CA1–3 of the Hyper + ischemia group were significantly higher than those in the Normo + ischemia group. HO-1 immunoreactivity in the Hyper + ischemia group was significantly increased in pyramidal neurons and astrocytes with time after ischemia, and the immunoreactivity was significantly higher than that in the Normo + ischemia group. In the Normo + Ischemia group, neuronal death was shown in pyramidal neurons located only in CA1 at 5 days after ischemia. However, in the Hyper + ischemia group, pyramidal neuronal death occurred in CA1–3 at 2 days after ischemia. Taken together, our findings showed that brain ischemic insult during hyperthermic condition brings up earlier and severer neuronal damage/death in the hippocampus, showing that HO-1 expression in neurons and astrocytes is different according to brain subregions and temperature condition. Based on these findings, we suggest that hyperthermia in patients with ischemic stroke must be taken into the consideration in the therapy.

Highlights

The brain has neurons that are very vulnerable to transient ischemia, which deprives the neurons of oxygen supply, decreases metabolic rate and gives an insufficient reserve of high-energy carbohydrates when compared to other tissues [1]
Neurons in the hippocampal formation following transient global brain or forebrain ischemia are distinctly different in terms of their susceptibility to ischemic insult according to their hippocampal sub-regions [3]
Transient forebrain ischemia in gerbils is induced by temporary occlusion (5–15 min) of both common carotid arteries alone, because the gerbils lack the circle of the Willis formation between the carotid and vertebral circulations [2]

Summary

Introduction

The brain has neurons that are very vulnerable to transient ischemia (ischemiareperfusion), which deprives the neurons of oxygen supply, decreases metabolic rate and gives an insufficient reserve of high-energy carbohydrates when compared to other tissues [1]. It has been suggested that hyperthermia leads to more severe brain injury following ischemia through calcium influx into neurons, releases of neurotoxic excitatory neurotransmitters and reactive oxygen species, and dysfunction of vascular permeability [8,9]. In a gerbil model of transient ischemia in the forebrain (telencephalon), hyperthermia conditioning before and during the transient ischemia led to more severe neuronal damage and glial activation in the hippocampus [14]. For the mechanisms of ischemic damage under hyperthermia, it has been proposed that vascular permeability dysfunction, the releases of neurotoxic excitatory neurotransmitters, the production of reactive oxygen species, and calcium influx into neurons can lead to more severe tissue injury [15,16,17]. The exact mechanisms of brain tissues or cells following ischemia-reperfusion under hyperthermia are not yet fully understood

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