Hypothermia protects the brain from transient global ischemia/reperfusion by attenuating endoplasmic reticulum response-induced apoptosis through CHOP.

Endoplasmic reticulum (ER) stress has been implicated in the pathology of cerebral ischemia. Apoptotic cell death occurs during prolonged period of stress or when the adaptive response fails. Hypothermia blocked the TNF or Fas-mediated extrinsic apoptosis pathway and the mitochondria pathway of apoptosis, however, whether hypothermia can block endoplasmic reticulum mediated apoptosis is never known. This study aimed to elucidate whether hypothermia attenuates brain cerebral ischemia/reperfusion (I/R) damage by suppressing ER stress-induced apoptosis. A 15 min global cerebral ischemia rat model was used in this study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in hippocampus CA1 were assessed after reperfusion of the brain. The expressions of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) in ischemic hippocampus CA1 were measured at 6, 12, 24 and 48 h after reperfusion. The results showed that hypothermia significantly attenuated brain I/R injury, as shown by reduction in cell apoptosis, CHOP expression, and increase in GRP78 expression. These results suggest that hypothermia could protect brain from I/R injury by suppressing ER stress-induced apoptosis

Neuronal apoptosis in CA1 region of hippocampus induced by global cerebral ischemia.

<p>Detection of apoptosis in hippocampus CA1 pyramidal neurons was carried out using Tunel staing. The sham group showed a large number of neurons and almost no TUNEL-positive cells (5.1±1.2) (A). In ischemia (C) and hypothermia (B) groups, the number of neurons were decreased and substantial TUNEL-positive cells were detected. The number of TUNEL-positive cells in hypothermia group (34.4±4.2) (B) is more than in ischemia group (40.5±5.7) (C), /400×visual field.</p

Expression of chop in hippocampus CA1.

<p>(a) Immunohistochemistry showed the chop was barely detected in sham group (A).The expression of chop in hypothermia group (B) is much weaker than that in ischemia group (C) at reperfusion 24 hours. /400×visual field (b) Western blot analysis showed that the chop was barely detected in sham group. In brains of ischemia group, it was increased 6 hour after 15 minutes of ischemia and gradually decreased thereafter; however, the degree of increase was much smaller in the hypothermia brains. (c) Quantitative analysis of Western blotting showed that hypothermia after ischemia significantly decreased chop after 15 minutes of ischemia (P<0.05 compared with ischemia brains at the same time points. 6 rats from each group at every time points were used for analysis).</p

Neurons in hippocampus CA1 area.

<p>(a) The picture showed the neurons in hippocampus CA1 area. The neurons in sham group (A) displayed regular appearance with large and round nuclei but pyknosis was observed in ischemia (C) and hypothermia group (B). (b) Compared with sham group(89.3±6.1) (A), the number of normal neuronal is fewer and the neurons of morphologic abnormality is more in ischemia group(47.3±4.5) (C). The number of survival neurons in hypothermia group(64.5±7.5) (B) is more than that in ischemia group. /400×visual field.</p