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

Abstract

Heat acclimation (HA) offers functional neuroprotection in mice after traumatic brain injury (TBI). This study further characterizes endogenous neuroprotection acquired by HA (34±11C, 30 d) after TBI. We establish here the ability of HA to induce sustained functional benefits and to reduce activation of apoptotic pathways. Neurobehavioral recovery, assessed by the Neurological Severity Score, was greater in HA mice up to 8 days after injury as compared with normothermic controls (P < 0.05) and lesion volume was also smaller in the HA group (P < 0.05). Reduced apoptotic cell death in HA mice was confirmed using caspase-3 activity measurements and immunohistochemistry. To investigate the underlying molecular pathways, expression levels of intrinsic apoptotic pathway-related proteins were examined. HA mice displayed higher mitochondrial levels of antiapoptotic Bcl-xL, accompanied by lower proapoptotic Bad levels and decreased cytochrome c release, suggesting a higher apoptotic threshold. Taken together with our previous reports, indicating increased Akt phosphorylation and antioxidative capacity, alongside with reduced tumor necrosis a levels after TBI in HA animals, the current results support the involvement of an antiapoptotic effect in HA-induced neuroprotection. Current results warrant further study as TBI-induced apoptosis may persist over weeks after injury, possibly providing a target for belated therapeutic intervention.

Long-lasting protection in brain trauma by endotoxin preconditioning

“…Notably, we as well as earlier studies addressing preconditioning in TBI (Perez-Pinzon et al, 1999;Shein et al, 2007Shein et al, , 2008Umschwief et al, 2010) have been using models of cerebral contusions in which a core lesion is surrounded by an area (traumatic penumbra) of reduced cerebral blood flow (Assaf et al, 1999;Kochanek et al, 2002;Yamakami and McIntosh, 1989). We do not know whether the target of preconditioning neuroprotection after TBI is the area around the contusion characterized by reduced cerebral blood flow and thus similarly to ischemic tissue.…”

“…In the setting of TBI, preconditioning has been scarcely investigated so far. However, the observation that endogenous neuroprotection can be elicited by transient ischemia (Perez-Pinzon et al, 1999) or by heat acclimation before the injury (Shein et al, 2007(Shein et al, , 2008Umschwief et al, 2010) indicates that this may be a relevant mechanism to induce a protective phenotype in this condition too.…”

Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

“…AT 2 transactivates TrkA 4 to induce Akt phosphorylation, 40 which may be followed by HIF-1a induction. HA enhances NGF signaling owing to increased TrkA and NGF levels, which coincide with the upregulation of Akt and HIF-1a levels, leading to a protected basal state.…”

“…Sample preparation was performed as previously described. 2 After homogenization in a buffer containing sucrose 0.25 mol/L, Tris 20 mmol/L (pH ¼ 7.6), MgCl 2 1.5 mmol/L, glycerol 10%, and ethylenediaminetetraacetic acid 1 mmol/L, samples were centrifuged at 5,000 r.c.f. for 10 minutes, and supernatants were stored at À 80 1C until analysis.…”

“…1 After TBI, HA mice display hypothermia, improved motor recovery, and cognitive state as well as reduced lesion volume and edema formation. 1,2 The molecular mechanisms underlying neuroprotection include reduced inflammation and apoptosis, 1,2 along with induction of hypoxia-inducible factor 1a (HIF-1a), brain-derived neurotrophic factor (BDNF), Akt phosphorylation, and erythropoietin signaling. Given the indispensable role of HIF-1a in HA-mediated neuroprotection, 1 we hypothesized that an upstream mediator of HIF-1a may coordinate neuroprotective elements.…”