Effect of therapeutic mild hypothermia on the genomics of the hippocampus after moderate traumatic brain injury in rats.
BACKGROUND
Traumatic brain injury (TBI), a major cause of morbidity and mortality, is a serious public health concern.


OBJECTIVE
To evaluate the effect of mild hypothermia on gene expression in the hippocampus and to try to elucidate molecular mechanisms of hypothermic neuroprotection after TBI.


METHODS
Rats were subjected to mild hypothermia (group 1: n = 3, 33 degrees C, 3H) or normothermia (group 2: n = 3; 37 degrees C, 3H) after TBI. Six genome arrays were applied to detect the gene expression profiles of ipsilateral hippocampus. Functional clustering and gene ontology analysis were then carried out. Another 20 rats were randomly assigned to 4 groups (n = 5 per group): group 3, sham-normothermia; group 4, sham-hypothermia; group 5, TBI-normothermia; and group 6, TBI-hypothermia. Real-time fluorescent quantitative reverse-transcription polymerase chain reaction was used to detect specific selected genes.


RESULTS
We found that 133 transcripts in the hypothermia group were statistically different from those in the normothermia group, including 57 transcripts that were upregulated and 76 that were downregulated after TBI (P < .01). Most of these genes were involved in various pathophysiological processes, and some were critical to cell survival. Analysis showed that 9 gene ontology categories were significantly affected by hypothermia, including the most affected categories: synapse organization and biogenesis (upregulated) and regulation of inflammatory response (downregulated). The mRNA expression of Ank3, Cmbp, Nrxn3, Tgm2, and Fcgr3 was regulated by hypothermia, TBI, or a combination of TBI and hypothermia compared with the sham-normothermia group. Their mRNA expression was significantly regulated by hypothermia in TBI groups.


CONCLUSIONS
Posttraumatic mild hypothermia has a significant effect on the gene expression profiles of the hippocampus, especially those genes belonging to the 9 gene ontology categories. Differential expression of those genes may be involved in the most fundamental molecular mechanisms of cerebral protection by mild hypothermia after TBI.
Feng
Jun-feng
JF
Department of Neurosurgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Zhang
Kui-ming
KM
Jiang
Ji-yao
JY
Gao
Guo-yi
GY
Fu
Xi'an
X
Liang
Yu-min
YM
D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D023281:Genomics / Q000379:methods; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D009419:Nerve Tissue Proteins; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2