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ABSTRACT: Increasing evidence has shown that mild hypothermia is neuroprotective for comatose patients resuscitated from cardiac arrest, but the mechanism of this protection is not fully understood. The aim of this study was to determine whether prolonged whole-body mild hypothermia inhibits mitochondrial membrane permeability (MMP) in the cerebral cortex after return of spontaneous circulation (ROSC). Thirty-seven inbred Chinese Wuzhishan minipigs were successfully resuscitated after 8 minutes of untreated ventricular fibrillation (VF) and underwent recovery under normothermic (NT) or prolonged whole-body mild hypothermic (HT; 33°C) conditions for 24 or 72 hours. Cerebral samples from the frontal cortex were collected at 24 and 72 hours after ROSC. Mitochondria were isolated by differential centrifugation. At 24 hours, relative to NT, HT was associated with reductions in opening of the mitochondrial permeability transition pore, release of pro-apoptotic substances from mitochondria, caspase 3 cleavage, apoptosis, and neurologic deficit scores, as well as increases in mitochondrial membrane potential and mitochondrial respiration. Together, these findings suggest that mild hypothermia inhibits ischemia-induced increases in MMP, which may provide neuroprotection against cerebral injury after cardiac arrest.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 March 2013; doi:10.1038/jcbfm.2013.33.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2013; · 5.46 Impact Factor
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ABSTRACT: To explore the molecular mechanisms by which mild hypothermia following resuscitation improves neurological function in a porcine model of cardiac arrest.
Thirty-three inbred Chinese Wuzhishan (WZS) minipigs were used. After 8 min of untreated ventricular fibrillation (VF), the surviving animals (n=29) were randomly divided into two groups including serum group (n=16) and molecular group (n=13). Serum group animals were used to measure porcine-specific tumour necrosis factor-alpha (TNF-α), interleukin (IL-6, IL-10), matrix metalloproteinase (MMP9), Aquaporin-4 (AQP4), tissue inhibitor to metalloproteinase-1 (TIMP1), neuron-specific enolase (NSE) and S100B at 0.5 h, 6 h, 12 h, 24 h and 72h recovery by enzyme-linked immunosorbent assay (ELISA). Molecular group animals were used to measure cerebral cortex messenger RNA (mRNA) and protein expression of nuclear factor-κB (NF-κB), MMP9 and AQP4 by real-time (RT) quantitative polymerase chain reaction (PCR) and Western blotting at 24 h and 72 h recovery. Animals were further divided into either normothermia or hypothermia groups. Hypothermia (33°C) was maintained for 12 h using an endovascular cooling device. Swine neurologic deficit scores (NDS) were used to evaluate neurological function at 24-h and 72-h recovery.
Twenty-nine of the 33 (87.9%) animals were successfully resuscitated. The hypothermia group exhibited higher survival rates at 24 h (75%) and 72 h (62.5%) compared to the normothermia group (37.5% and 25%, respectively). Hypothermia markedly inhibited expression of NF-κB, TNF-α, MMP9 and NSE, and promoted expression of TIMP1 (P<0.01). The mean NDS at 24-h and 72-h recovery was 112.5 and 61, respectively, in the hypothermic group, and 230 and 207.5, respectively, in the normothermia group.
Brain protection induced by hypothermia involves inhibition of inflammatory and brain edema pathways.
Resuscitation 01/2012; 83(7):913-20. · 3.60 Impact Factor
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ABSTRACT: Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33°C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation.
PLoS ONE 01/2012; 7(4):e35313. · 4.09 Impact Factor
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ABSTRACT: Mild induced hypothermia (MIH) is recommended to treat neurologic injury after cardiac arrest (CA). However, clinical trials to assess MIH benefit after CA have been largely inconclusive. We investigated the subsequent changes in cerebrospinal fluid (CSF) biochemistry after MIH (33°C-34°C for 12 hours) and evaluated the importance of ongoing fever control.
Thirty-two male Wuzhishan inbred mini pigs (n = 16/group) underwent ventricular fibrillation followed by cardiopulmonary resuscitation and were randomized into 2 groups: hypothermic and control. Upon resumption of spontaneous circulation (ROSC) from CA, the hypothermic group was treated with MIH by endovascular cooling. The control group received no temperature intervention. Core temperatures were continually monitored. At various points throughout the procedure, CSF samples were obtained to measure glutamate, lactate, and pyruvate levels.
The core temperature of the hypothermic group was found to have increased postrewarming and reached levels comparable with those of the control group at ROSC 72 hours. In both groups, glutamate increased significantly after ROSC, but the glutamate levels in the hypothermic group were lower than those in the control group, except at ROSC 1 hour. The lactate-pyruvate ratio increased in the control group at ROSC 1 hour and was significantly lower in the hypothermic group (P < .05).
Mild induced hypothermia mitigated and delayed the CA-induced increase of CSF glutamate. Therefore, our results suggest that clinically inducing hypothermia as soon as possible after CA, or prolonging the time of MIH in combination with controlling ongoing fever, may enhance hypothermic protective effects.
The American journal of emergency medicine 12/2011; 30(8):1420-8. · 1.54 Impact Factor
