Heat Acclimation Increases Hypoxia-Inducible Factor 1α and Erythropoietin Receptor Expression: Implication for Neuroprotection after Closed Head Injury in Mice

Abstract

Experimental evidence indicates that long-term exposure to moderately high ambient temperature (heat acclimation, HA) mediates cross-tolerance to various types of subsequently applied stress. The transcriptional activator hypoxia-inducible factor 1 (HIF-1) has been implicated in playing a critical role in HA. It also regulates the expression of Erythropoietin (Epo), whose neuroprotective effects have been shown in a variety of brain injuries. The aim of the present study was to examine whether HA exerts a beneficial effect on the outcome of closed head injury (CHI) in mice and to explore the possible involvement of HIF-1 and Epo in this process. Heat acclimated mice and matched normothermic controls were subjected to CHI or sham surgery. Postinjury motor and cognitive parameters of acclimated mice were compared with those of controls. Mice were killed at various time points after injury or sham surgery and brain levels of HIF-1a, the inducible subunit of HIF-1, Epo, and the specific erythropoietin receptor (EpoR) were analyzed by Western immunoblotting. Motor and cognitive functions of acclimated mice were significantly better than those of controls. Heat acclimation was found to induce a significant increase in expression of nuclear HIF-1a and EpoR. The EpoR/Epo ratio was also significantly higher in acclimated mice as compared with controls. Nuclear HIF-1a and EpoR were higher in the acclimated group at 4 h after injury as well. The improved outcome of acclimated mice taken together with the basal and postinjury upregulation of the examined proteins suggests the involvement of this pathway in HA-induced neuroprotection.

Heat Acclimation Provides Sustained Improvement in Functional Recovery and Attenuates Apoptosis after Traumatic Brain Injury

“…Previously, we have shown that HA induces a neuroprotective effect in both rats and mice, reflected by reduced tissue edema formation and improved functional recovery during the initial 24 to 72 h after impact (Shein et al, 2005;Shohami et al, 1994). Our current findings further expand these previous ones, and show that enhanced recovery of function by HA Figure 3 Effect of heat acclimation and closed head injury (CHI) on Bcl-xL and Bad mRNA levels.…”

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

“…Such a model mimics several pathophysiological characteristics of human focal cortical contusion (Nag, 1996) and produces a reproducible, demarcated lesion to the neocortex that allows evaluation of the efficacy of compounds with a neuroprotective potential (Hortobagyi et al, 2000). The present findings extend previous work by showing that rHuEPO significantly reduces brain injury and improves neurological recovery following traumatic insults (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). In particular, rHuEPO administration improved both functional and cognitive recovery of the rats with an effect that was significantly shown since the early stage after TBI and lasted for 15 days.…”

“…Although the role of EPO as a neuroprotectant has been studied extensively in a wide range of in vitro and in vivo models of brain injury, up to date, there are only few studies evaluating the effect of rHuEPO after experimental TBI (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005) and none has used a cryogenic injury paradigm. Neurobehavioral improvement after EPO administration has been reported in other studies where different models of brain injury were used.…”

“…In this scenario, a large body of evidence has pointed out the efficacy of the hormone erythropoietin (EPO) as neuroprotectant. Although peripherally administered recombinant human EPO (rHuEPO) has shown to penetrate the blood-brain barrier (BBB) and reduce brain injury following a variety of insults (Brines et al, 2000;Digicaylioglu and Lipton, 2001;Grasso et al, 2004), its potential neuroprotective efficacy in an in vivo model of experimental TBI has been scarcely investigated (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). Evidence shows widespread efficacy of rHuEPO in injury models of spinal cord (Celik et al, 2002;Gorio et al, 2002;Grasso et al, 2006), subarachnoid hemorrhage (Buemi et al, 2002a,b;Catania et al, 2002;Grasso, 2001;Grasso et al, 2002a,b;Springborg et al, 2002), retina, and the heart damage (Calvillo et al, 2003;Junk et al, 2002).…”

Neuroprotective effects of erythropoietin in patients with severe closed brain injury

“…Although peripherally administered recombinant human Epo (rhEpo) has shown to penetrate the blood-brain barrier and reduce brain injury (4, 17), its potential neuroprotective efficacy in an in vivo model of experimental TBI has been rarely investigated (4, 26,30,31). In addition, there are numerous studies regarding the widespread efficacy of rhEpo in injury models of spinal cord (14, 18) and subarachnoid hemorrhage (15,17,33) promoting the role of Epo as an essential mediator of protection in the central nervous system (CNS).…”