Heat acclimation provides sustained improvement in functional recovery and attenuates apoptosis after traumatic brain injury.
Heat acclimation (HA) offers functional neuroprotection in mice after traumatic brain injury (TBI). This study further characterizes endogenous neuroprotection acquired by HA (34+/-1 degrees C, 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 alpha 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.
Umscheif
Gali
G
Umschwief
Gali
G
Department of Pharmacology, The Hebrew University, Jerusalem, Israel.
Shein
Na'ama A
NA
Alexandrovich
Alexander G
AG
Trembovler
Victoria
V
Horowitz
Michal
M
Shohami
Esther
E
D000064:Acclimatization / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D006321:Heart / Q000503:physiopathology; D006358:Hot Temperature; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D020127:Recovery of Function / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051025:bcl-Associated Death Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
D000975:Antioxidants; D012333:RNA, Messenger; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3