Preinduction of HSP70 promotes hypoxic tolerance and facilitates acclimatization to acute hypobaric hypoxia in mouse brain

Abstract

It has been shown that induction of HSP70 by administration of geranylgeranylacetone (GGA) leads to protection against ischemia/reperfusion injury. The present study was performed to determine the effect of GGA on the survival of mice and on brain damage under acute hypobaric hypoxia. The data showed that the mice injected with GGA survived significantly longer than control animals (survival time of 9.55 +/- 3.12 min, n = 16 vs. controls at 4.28 +/- 4.29 min, n = 15, P < 0.005). Accordingly, the cellular necrosis or degeneration of the hippocampus and the cortex induced by sublethal hypoxia for 6 h could be attenuated by preinjection with GGA, especially in the CA2 and CA3 regions of the hippocampus. In addition, the activity of nitric oxide synthase (NOS) of the hippocampus and the cortex was increased after exposure to sublethal hypoxia for 6 h but could be inhibited by the preinjection of GGA. Furthermore, the expression of HSP70 was significantly increased at 1 h after GGA injection. These results suggest that administration of GGA improved survival rate and prevented acute hypoxic damage to the brain and that the underlying mechanism involved induction of HSP70 and inhibition of NOS activity.

Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

“…Hsp70 proteins are produced mainly in endothelial cells, in the core of infarcts in the cells that are most resistant to ischemia, in glial cells at the edges of infarcts, and in neurons outside the areas of infarction (479). It has been suggested that this neuronal expression of Hsp70 outside an infarct can be used to define the ischemic penumbras, which means the zone of protein denaturation in the ischemic areas; consistently in in vivo transgenic mice overexpressing Hsp70, compared to wild-type mice in a middle cerebral artery occlusion model of permanent cerebral ischaemia, it has been demonstrated that overexpression of Hsp70 reduces the overall lesion size and also limits the tissue damage within the lesion (479).…”

The protective role of 5-hydroxymethyl-2-furfural (5-HMF) against acute hypobaric hypoxia

“…Mice were acclimatized in the chambers in room air for 30 min to 1 h before experiments. Two altitudes were selected based on trials and previous reports (Zhang et al 2004(Zhang et al , 2009) to create hypoxic conditions in the chambers: (1) 9,500 m (5.2% O 2 ) at a velocity of approximately 45 m/s for lethal acute hypobaric hypoxia, under which untreated mice died in a relatively uniform time period, and (2) the altitude of 8,300 m (7.0% O 2 ) at a velocity of approximately 20 m/s for sublethal acute hypobaric hypoxia, as it was severe enough to induce typical hypoxic organ injuries yet allowed the mice to survive so that hypoxia-induced changes in permeability of BBB, histological pathology, and the level of protein could be analyzed (Zhang et al 2009). …”

Tolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia in rats

“…Shrivastava et al [22] developed a model of acute hypobaric hypoxia in rats with a simulated altitude of 10,668 m. During the experiment, the agonal breathing time and LD in hypoxia were recorded. The same method was also applied to mice, which were exposed to an altitude of 10,000 m and hypoxia simulation at a rate of 50 m/s for 15 min; the absolute apnea and death time were registered [28]. Lukyanova et al [13] and Mironova et al [16] modeled acute hypobaric hypoxia at a simulated altitude of 11,500 m and registered the onset of agonal breathing time.…”