Spontaneous hypothermia ameliorated inflammation and neurologic deficit in rat cardiac arrest models following resuscitation
- Authors:
- Published online on: November 20, 2017 https://doi.org/10.3892/mmr.2017.8113
- Pages: 2127-2136
-
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Cardiac arrest (CA), also termed cardiopulmonary arrest, is a sudden stop in effective blood circulation, due to the failure of the heart to effectively contract or to contract at all. CA remains a major public health issue and is the most common direct cause of mortality in Western and developing countries (1,2). Overall survival of cardiac arrest patients outside of a hospital setting is only ~6.4% (3). This low rate is due to the initial difficulty in restoring hemodynamic stability (4), as well as to a high incidence of severe neurologic deficits caused by the CA (5). Therefore, <30% of survivors are able to return to a normal functioning lifestyle (6).
The brain injury that results from the return of spontaneous circulation (ROSC) is a complicated process. The overall mechanisms remain elusive, but include altered Ca2+ homeostasis, free radical formation, mitochondrial dysfunction, protease activation, altered gene expression and inflammation (7,8). These then lead to neuronal death in the central nervous system. Among all the potential mechanisms, inflammation stands out, as it is correlated with postischemic neuronal apoptosis (9). NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), a component of the inflammasome, has been reported to function as a pathogen recognition receptor that recognizes pathogen-associated molecular patterns (10,11). The inflammasome complex is a central component of the innate immune response via regulation of interleukin (IL)-1β, IL-18 and pyroptosis (12). NLPR3 is significant in ischemia-reperfusion injuries in many tissue types, including renal (13), brain (14) and spinal cord (15). In the cerebral cortex, activation of the NLRP3-inflammasome induces the processing and release of IL-1β and IL-18 (16). Deletion of NLRP3 may ameliorate the neurovascular damage in ischemic stroke mice (17). Therefore, ischemic neural deficits caused by CA may also be mitigated via inhibition of NLRP3.
Hypothermia is defined as a body core temperature <35.0°C and has been known to be a potent putative neuroprotectant (18). Mild hypothermia (33°C) inhibits ischemia-induced promotion of mitochondrial membrane permeability, which may provide neuroprotection against cerebral injury following CA (19). Spontaneous hypothermia (SH) is clinically associated with the risk of mortality (20). Hickey et al (21) demonstrated that rats resuscitated from asphyxial CA developed neuroprotective SH (21). However, whether the neural deficit resulting from CA was correlated with activation of the inflammasome and was ameliorated by SH remains unclear. In the present study, the neural damage alterations and inflammasome component expression levels were elucidated following ROSC in established CA rat models. In addition, the role of SH in the inhibition of inflammasome component expression, and the amelioration of the neurologic deficit and neuronal death in the cerebral cortex were determined. The aim of the present study was to investigate the underlying mechanisms of ROSC-induced neurological deficits, and assess the potential strategies for the prevention and treatment of post-CA syndrome.
Materials and methods
Grouping
In total, 84 male specific pathogen-free grade Sprague Dawley rats (weight, 350–400 g; age, 8 weeks) were purchased from the Laboratory Animal Center of Guangzhou University of Chinese Medicine (Guangzhou, China). Firstly, 18 rats were randomly separated into three groups as follows: Group I, control group; Group II, the CA model group that received cardiopulmonary resuscitation (CPR) 4 min after CA; and Group III, the CA model group, which received CPR 6 min after CA. Secondly, 36 rats were then randomly separated into two groups, including 6 control rats and 30 CA model rats. CPR was conducted 6 min after CA. The CA rats were equally sub-divided into five groups, according to the different time points (6, 12, 24, 48 and 72 h) after ROSC. Thirdly, 30 rats were randomly divided into two groups, including six control rats and 24 CA model rats. These CA rats were equally sub-divided into SH group and controlled normothermia (CN) group. The SH and CN groups were again divided into two, determined by 24 h (SH Group I and CN Group I) or 48 h (SH Group II and CN Group II) after ROSC. The mortality rate of rats during the preparation of rat models was 6.7%. The present study was approved by the ethics committee of Sun Yat-Sen University (Guangzhou, China).
CA rat model
Rat CA and resuscitation were performed, as previously described (21,22). Anesthesia was achieved using 45 mg/kg pentobarbital sodium. Animals were ventilated with a Harvard Rodent Ventilator (Harvard Apparatus, Holliston, MA, USA), and the temperature was measured and maintained at 37±0.5°C throughout the preparation, insult, and first hour of recovery. Prior to asphyxia, the anesthetic gases were washed out with 3 min of ventilation at 100% oxygen, followed by 2 min of room air. Vecuronium was administered prior to asphyxia, in order to prevent reflex respiratory efforts during asphyxia. Subsequent to the washout period, animals were asphyxiated by disconnecting the respiratory tubing from the ventilator for 6 min, resulting in ~5 min of CA.
Resuscitation
Following exactly 5 min, the ventilator was reconnected and ventilation was resumed with oxygen at a rate of 60 breaths/min. Intravenous epinephrine (0.005 mg/kg) and bicarbonate (1.0 mEq/kg) were administered, and external chest compressions were performed at a rate of 250–300 compressions/min. Rats generally experienced a ROSC within 2 min. If not, an additional dose of epinephrine was administered. Following stabilization for at least 60 min and confirmation of adequate spontaneous respirations, rats were extubated and weaned from oxygen back to room air.
Temperature control
In the CN group, rats were maintained at 37±0.5°C during CA and for 4 h after resuscitation. In the SH group, rats were maintained at 37°C during CA, but following resuscitation were allowed to regulate their own temperature.
Neurologic deficit scale (NDS) score measurement
General neurologic status was assessed using the validated NDS at 24, 48, and 72 h after CA (23). The score includes an assessment of consciousness, respiration, cranial nerve activity, motor and sensory function, and coordination. Normal rats have an NDS of zero.
Enzyme-linked immunosorbent assay (ELISA)
Arterial blood samples (10 ml) were drawn at different time points after ROSC. Concentration changes in serum S100 calcium-binding protein B [S100B; cat. no. H6-KA0037, Multi Sciences (Lianke) Biotech Co., Ltd., Hangzhou, China], IL-1β [cat. no. 70-EK201B1/2, Multi Sciences (Lianke) Biotech Co., Ltd.] and IL-18 (cat. no. RK-KOA0362; Rockland Immunochemicals, Inc., Limerick, PA, USA) in the cerebral cortex were monitored by ELISA for the different groups. After coating with coating buffer (50 mmol/l sodium carbonate buffer, pH=9.6), plates were sequentially washed with phosphate buffered saline with 0.05% Tween-20 (PBST) buffer (cat. no. A100235-0001; Sangon Biotech Co., Ltd., Shanghai, China), blocked with 1% bovine serum albumin (BSA; cat. no. A602440-0050, Sangon Biotech Co., Ltd.), and incubated for 1 h at 37°C. Anti-S100B (1:200), anti-IL-1β (1:200) or anti-IL-18 antibodies (1:100), and horseradish peroxidase-conjugated antibody (1:1,000; all included in the corresponding ELISA kit) were sequentially added and incubated for 1 h at 37°C. The chromogenic substrate 3,3′,5,5′-Tetramethylbenzidine was added for detection. Absorbance was measured at a wavelength of 450 nm using an EnSpire multimode plate reader (Perkin Elmer, Waltham, Massachusetts).
Western blotting
Tissue samples were lysed in radioimmunoprecipitation buffer (50 mM Tris-HCl buffer pH 7.4, 150 mM NaCl, 5 mM EDTA, 1% NP-40 and 0.25% sodium deoxycholate). Total protein was extracted from tissue lysate by centrifugation at 12,000 × g for 10 min at 4°C and protein concentrations were measured using a Bicinchoninic Acid assay (Sangon Biotech Co., Ltd.) according to the manufacturer's instructions. A total of 2 µg protein was loaded onto each lane of 10% polyacrylamide gel (250V voltage for 2 h) and blotted onto a polyvinylidene difluoride (PVDF) membrane. After blocking with PBST containing 5% nonfat dry milk, the membrane was incubated with antibodies against NLRP3 (cat. no. 13158; 1:500), apoptosis-associated speck-like protein containing a CARD (ASC; cat. no. 67824; 1:500), caspase-1 (cat. no. 2225; 1:400), caspase-3 (cat. no. 9662; 1:500), and β-tubulin (cat. no. 2146; 1:500; all Cell Signaling Technology, Inc., Danvers, MA, USA). Peroxidase-linked anti rabbit IgG (Thermo Fisher Scientific, Inc., Waltham, MA, USA) served as a secondary antibody. These proteins were visualized using an ECL western blotting detection kit (GE Healthcare, Chicago, IL, USA).
Immunohistochemistry
The rats were anesthetized with an overdose of 150 mg/kg pentobarbital and then sacrificed. The whole brain was immediately removed and frozen on dry ice. Then, the cerebral cortex site was separated from the whole brain. The sections of the cerebral cortex (~1.5 cm3) were sequentially washed in dimethylbenzene and ethanol, before being blocked in 3% H2O2. All nonspecific binding sites were blocked for 30 min in PBS with 5% BSA. The sections were then incubated at 4°C with anti-NLRP3, anti-ASC, anti-caspase-1, or anti-caspase-3 antibodies (Cell Signaling Technology, Inc.) overnight. Biotin-conjugated secondary antibody (cat. no. ab97044; Abcam, Cambridge, MA, USA) was applied to the slides and incubated for 1 h at room temperature. Finally, 3,3′-diaminobenzidine (DAB)/H2O2 was added to the surface of the slide to develop the color at room temperature for 10 min. The slides were visualized using a Nikon ECLIPSE 90i.
TUNEL assay
Sections were perfused with dimethylbenzene and sequentially washed with different concentrations of ethanol and blocked in 3% H2O2. These sections were incubated in 5% BSA for 30 min and the fragmented DNA was labeled with the TUNEL reaction solution at 37°C for 1 h. Converter-peroxidase was added to the sections at 37°C for 30 min before the TUNEL-positive nuclei were visualized by adding the DAB staining solution. All images were captured using a Nikon ECLIPSE 90i.
Statistical analysis
Data are presented as means ± standard error of the mean and analysis was performed with GraphPad Prism 6 software (GraphPad Software, Inc., La Jolla, CA, USA). The normalized intensity for western blotting bands was measured with Image J software version 1.45 (National Institutes of Health, Bethesda, MD, USA). Unpaired Student's t-tests and one-way ANOVA with a Tukey post hoc test were used to determine significant differences. P<0.05 was considered to indicate a statistically significant difference.
Results
Increasing duration of CA aggravated neural defects
In order to elucidate the role of CA in neural defects, physiological parameters were compared between the control group and the two asphyxia groups, determining that there was no significant difference in physiological parameters among the three groups (Table I). Similarly, no apparent alteration in the majority of physiological parameters was observed between the two asphyxia groups following resuscitation. However, the duration of ROSC and the duration without blood flow in the asphyxia group that received CPR at 6 min after CA (Group III) was significantly longer than in the asphyxia group that received CPR at 4 min after CA (Group II; Table II). In addition, it was found that anal temperature was lower in the two asphyxia groups when compared with the control group. In addition, the rectal temperature in Group III was lower than that in Group II at five consecutive time points (from 10–120 min), but not at 180 min after ROSC (Fig. 1A).
 | Table I.Comparison of physiological parameters between Group I (Sham) and Groups II and III (the asphyxia groups). |
Subsequently, it was determined whether the various neural defects were present in the asphyxia models. As shown in Fig. 1B, the NDS score was significantly lower in Group III than in Group II at 24, 48 and 72 h after CPR. Additionally, the S100B serum concentration of Group II and III was significantly greater than that in Group I at 72 h after CPR (Fig. 1C). The immunohistochemistry results indicated that cell morphology in the cerebral cortex was normal in the control (Group I; Fig. 1D). By contrast, morphological damage was observed in the cerebral cortex of Group II, including a vacuole and swelling in the cytoplasm (Fig. 1E). Further severe damage was observed in Group III, where necrosis was observed in the cells of cerebral cortex (Fig. 1F). These data demonstrated that increasing duration of CA increased the severity of neural damage in the cerebral cortex and enhanced the incidence of inflammation.
Dynamic expression patterns of NLRP3, ASC and caspase-1 following ROSC
As the observed neural defects were associated with inflammation, whether the expression levels of certain key inflammatory factors were altered following resuscitation in the CA models were investigated. The potential changes in physiological parameters between the control and five asphyxia groups that were resuscitated at different time points after ROSC were detected. No apparent changes in physiological parameters were observed among the six groups, as presented in Table III. Furthermore, no significant difference in duration of asphyxia and resuscitation among the six groups was observed (Table IV). Whether the expression levels of key components of the inflammasome, including NLRP3, ASC and caspase-1 were altered following ROSC were determined. The expression level of NLRP3 was constantly demonstrated to increase at different time points, except for 48 h after ROSC (Fig. 2A and B). In addition, it was found that the expression level of ASC significantly increased at 6 h after ROSC, but did not exhibit any subsequent further increase (Fig. 2A and C). The expression level of caspase-1 increased at 6 and 48 h after ROSC, but showed no further increase at 12, 24 or 72 h after ROSC compared with the previous time points (Fig. 2A and D). These findings were confirmed by immunohistochemical analysis. The number of ASC, NLRP3 and caspase-1 positive cells significantly increased at different time points after ROSC, compared with what was observed in the control (Fig. 3A). Collectively, these results indicate that the expression levels of NLRP3, ASC and caspase-1 increase with increasing time following ROSC, further enhancing inflammation.
| Table III.Comparison of physiological parameters among the sham group and five asphyxia groups at different time points after ROSC. |
| Table IV.Comparison of asphyxia and CPR duration among the five asphyxia groups with different time points after ROSC (n=6 per group). |
Concentrations of IL-1β and IL-18 increased in the cerebral cortex after ROSC
ELISA assays were performed to determine whether the concentrations of IL-1β and IL-18 in the cerebral cortex increased after ROSC. Compared with the control group, the concentration of IL-1β was significantly higher at 6 h and reached the maximal level at 12 h after ROSC (Fig. 3B). The concentration of IL-1β concentration gradually decreased at 24, 48 and 72 h after ROSC, but continued to be higher than that of the control group (Fig. 3B). Similarly, the IL-18 concentration was significantly higher after 6 h, and consistently increased with increasing time after ROSC (Fig. 3C). These data demonstrated that IL-1β and IL-18 concentrations were elevated in CA rat models after ROSC, indicating the aggravation of inflammation in the cerebral cortex.
SH alleviated neurological deficiency, apoptosis and inflammation in the CA rat model
Subsequently, the effects of SH on the neurological deficiency and inflammation observed in CA models were elucidated. No significant differences in physiological parameters were observed between the control, SH and CN groups (Table V). In the CA models, no apparent alteration in asphyxia time and CPR to ROSC time was identified, nor was any change observed in the tested physiological parameters among all four asphyxia groups following ROSC, as presented in Table VI. By contrast, the rectal temperature was significantly lower in the SH group than in the CN group (Fig. 4A). The NDS score was significantly higher in the SH group compared with the CN group at 24 and 48 h after ROSC (Fig. 4B). Additionally, the S100B concentration was shown to be reduced in the SH group compared with the CN group at 24 and 48 h after ROSC (Fig. 4C). Western blot analysis demonstrated that the expression levels of NLRP3, ASC, caspase-1 and caspase-3 markedly decreased in the SH groups compared with the CN group (Fig. 4D-H). Similar results were obtained via immunohistochemical analysis. The number of NLRP3, ASC, caspase-1 and caspase-3 positive cells in the SH group significantly decreased compared with the CN group (Fig. 5A). In addition, apoptosis was partially inhibited in the SH group, as the ratio of TUNEL-positive cells in this group was markedly reduced when compared with the CN group, while there was a limited number of apoptotic cells in the control group (Fig. 5B). Furthermore, SH after ROSC markedly decreased the concentrations of IL-1β and IL-18 (Fig. 5C). Finally, the cells in the cerebral cortex exhibited more severe damage in the CN group than did the cells in the SH group, while the cell morphology in the control group was normal (Fig. 5D). Thus, these data demonstrate that SH alleviated neural defects, apoptosis, and inflammation in the cerebral cortex, when compared with the CN group.
| Table V.Comparison of physiological parameters among the sham group and asphyxia groups with SH and CN. |
| Table VI.Comparison of asphyxia and resuscitation duration, as well as physiological parameters among the four asphyxia groups (n=6). |
Discussion
The present study demonstrates that the expression levels of inflammasome components changed in CA rat models following ROSC, potentially indicating the participation of the inflammasome in post-CA syndrome. In addition, it was found that spontaneous hypothermia mitigated the neural defects and inflammation induced by CPR and ROSC in CA models compared with the CN model, providing mechanistic exploration of the effect of SH on post-CA syndrome and its potential correlation with the inflammasome.
Hypothermia is common in patients with neurologic disorders and those in a critical condition. In the present study, hypothermia was demonstrated in the established CA rat models. This is consistent with previous findings showing that rats resuscitated from asphyxial CA developed mild to moderate hypothermia (21). An important factor leading to hypothermia is the duration of the perfusion without blood flow. It was identified that a longer duration of asphyxia prior to resuscitation caused a lower body temperature and thus a more serious neural deficit. Hypothermia is a double-edged sword, however, as SH exerted a protective effect against neurologic damage and inflammation in the CA models. Until now, hypothermia has only been a validated effective treatment for brain resuscitation following CA. There is no consensus on the specific duration of hypothermia in the treatment, but the generally accepted time is 12–24 h (24,25). Theoretically, longer durations of hypothermia are more beneficial to the neural tissues. However, there are side effects during the treatment, such as prolonged clotting time and pulmonary infection. Consistent with the current finding in rat models, Vijlbrief et al (26) identified that hypothermia following perinatal asphyxia exerted a beneficial effect on cardiac function in infants, indicating its potential clinical application.
CA induced increased expression levels of pro-inflammatory cytokines, therefore, aggravating the inflammatory reaction. In the hypothermia treatment, however, expression levels of inflammation-associated components are altered. Callaway et al (27) identified that SH alleviated the NDS in CA models, but concluded that altering the inflammatory response subsequent to CA is not necessary to achieve the beneficial effects of hypothermia (27). By contrast, NLRP3 expression was demonstrated to be lower in the SH group compared with the CN group, and the secretion of IL-18 and IL-1β was decreased in the SH group. This discrepancy is likely due to the different techniques used to initiate the asphyxia and trigger the activation of the NLRP3 inflammasome. Activation of the NLRP3 inflammasome depends on an increase in ATP provision and calcium load, while hypothermia may inhibit the calcium influx and upload (28). Therefore, SH following resuscitation may work via the above-mentioned mechanisms to inhibit the NLRP3 inflammasome, and potentially downstream IL-18 and IL-1β expression, to exert a neuroprotective effect. However, the specific mechanisms involved require further investigation.
Cell death or apoptosis occurs following ischemia or reperfusion. Previous reports have indicated that hypothermia inhibits caspase-3 mRNA expression (29). In the caspase family, caspase-1 participates in the inflammatory reaction and is responsible for the activation of pro-inflammatory cytokines, while caspase-3 mediates apoptosis (30). In the present study, CA caused upregulation of the expression level of caspase-1 and caspase-3; further demonstrating that inflammation and apoptosis were promoted by CA. The initiation of apoptosis occurs subsequent to inflammation. There is, therefore, enough time to intervene before CA induces apoptosis. Various types of treatments such as hypothermia may inhibit apoptosis via caspase-3 inhibition. The current study identified that expression levels of caspase-1 and caspase-3 decreased with SH in CA models. This result was similar to that observed in the hippocampus, where caspase-1 and caspase-3 expression increased following asphyxia. In recent years, combination therapy has been used to ameliorate neural disorders (31). Therefore, the present study provides solid evidence to support the potential clinical application of hypothermia. Future investigations will focus on survival prognosis, in order to determine whether hypothermia completely replaces the standard treatment for CA-induced neurologic deficits.
In conclusion, the present study demonstrates that SH ameliorated inflammation and neurologic deficit in CA models following resuscitation. The findings are important to increase understanding of the underlying mechanisms in CA-induced inflammation and neurologic damage following ROSC. Furthermore, the current findings promote a potential novel therapeutic strategy, which may be a promising candidate for increasing the survival rate and quality of life for patients suffering from post-CA syndrome.
Acknowledgements
The current study was supported by a research grant from project of Leading Talents in the Pearl River Talent Plan of Guangdong Province (grant no. 81000-42020004).
References
|
Berdowski J, Berg RA, Tijssen JG and Koster RW: Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 81:1479–1487. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Hua W, Zhang LF, Wu YF, Liu XQ, Guo DS, Zhou HL, Gou ZP, Zhao LC, Niu HX, Chen KP, et al: Incidence of sudden cardiac death in China: Analysis of 4 regional populations. J Am Coll Cardiol. 54:1110–1118. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Nichol G, Stiell IG, Laupacis A, Pham B, Maio VJ and Wells GA: A cumulative meta-analysis of the effectiveness of defibrillator-capable emergency medical services for victims of out-of-hospital cardiac arrest. Ann Emerg Med. 34:517–525. 1999. View Article : Google Scholar | |
|
Wang HE, Min A, Hostler D, Chang CC and Callaway CW: Differential effects of out-of-hospital interventions on short- and long-term survival after cardiopulmonary arrest. Resuscitation. 67:69–74. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Laver S, Farrow C, Turner D and Nolan J: Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med. 30:2126–2128. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V and Rowan K: Outcome following admission to UK intensive care units after cardiac arrest: A secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia. 62:1207–1216. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Neumar RW: Molecular mechanisms of ischemic neuronal injury. Ann Emerg Med. 36:483–506. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Johnson EM Jr, Greenlund LJ, Akins PT and Hsu CY: Neuronal apoptosis: Current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma. 12:843–852. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Mizushima H, Zhou CJ, Dohi K, Horai R, Asano M, Iwakura Y, Hirabayashi T, Arata S, Nakajo S, Takaki A, et al: Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1. J Comp Neurol. 448:203–216. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Lu A and Wu H: Structural mechanisms of inflammasome assembly. FEBS J. 282:435–444. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Martinon F: Detection of immune danger signals by NALP3. J Leukoc Biol. 83:507–511. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Rathinam VA, Vanaja SK and Fitzgerald KA: Regulation of inflammasome signaling. Nat Immunol. 13:333–342. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Shigeoka AA, Mueller JL, Kambo A, Mathison JC, King AJ, Hall WF, Correia Jda S, Ulevitch RJ, Hoffman HM and McKay DB: An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J Immunol. 185:6277–6285. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Xu Y, Sheng H, Bao Q, Wang Y, Lu J and Ni X: NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun. 56:175–186. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zendedel A, Johann S, Mehrabi S, Joghataei MT, Hassanzadeh G, Kipp M and Beyer C: Activation and regulation of NLRP3 Inflammasome by Intrathecal application of SDF-1a in a spinal cord injury model. Mol Neurobiol. 53:3063–3075. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, Zhou ML, Zhu L and Hang CH: Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 38:2072–2083. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q and Yi F: NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 34:660–667. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Liu L and Yenari MA: Therapeutic hypothermia: Neuroprotective mechanisms. Front Biosci. 12:816–825. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Gong P, Hua R, Zhang Y, Zhao H, Tang Z, Mei X, Zhang M, Cui J and Li C: Hypothermia-induced neuroprotection is associated with reduced mitochondrial membrane permeability in a swine model of cardiac arrest. J Cerebr Blood Flow Metad. 33:928–934. 2013. View Article : Google Scholar | |
|
Rubiano AM, Sanchez AI, Estebanez G, Peitzman A, Sperry J and Puyana JC: The effect of admission spontaneous hypothermia on patients with severe traumatic brain injury. Injury. 44:1219–1225. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Hickey RW, Ferimer H, Alexander HL, Garman RH, Callaway CW, Hicks S, Safar P, Graham SH and Kochanek PM: Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med. 28:3511–3516. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
D'Cruz BJ, Logue ES, Falke E, DeFranco DB and Callaway CW: Hypothermia and ERK activation after cardiac arrest. Brain Res. 1064:108–118. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Jia X, Koenig MA, Shin HC, Zhen G, Pardo CA, Hanley DF, Thakor NV and Geocadin RG: Improving neurological outcomes post-cardiac arrest in a rat model: Immediate hypothermia and quantitative EEG monitoring. Resuscitation. 76:431–442. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Drabek T, Janata A, Wilson CD, Stezoski J, Janesko-Feldman K, Tisherman SA, Foley LM, Verrier JD and Kochanek PM: Minocycline attenuates brain tissue levels of TNF-α produced by neurons after prolonged hypothermic cardiac arrest in rats. Resuscitation. 85:284–291. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Kida K, Shirozu K, Yu B, Mandeville JB, Bloch KD and Ichinose F: Beneficial effects of nitric oxide on outcomes after cardiac arrest and cardiopulmonary resuscitation in hypothermia-treated mice. Anesthesiology. 120:880–889. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Vijlbrief DC, Benders MJ, Kemperman H, van Bel F and de Vries WB: Cardiac biomarkers as indicators of hemodynamic adaptation during postasphyxial hypothermia treatment. Neonatology. 102:243–248. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Callaway CW, Rittenberger JC, Logue ES and McMichael MJ: Hypothermia after cardiac arrest does not alter serum inflammatory markers. Crit Care Med. 36:2607–2612. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Ding L, Gao X, Yu S and Yang J: Effects of mild and moderate hypothemia therapy on expression of cerebral neuron apoptosis related proteins and glial fiber acidic protein after rat cardio-pulmonary resuscitation. Cell Biochem Biophys. 70:1519–1525. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Lu J, Shen Y, Qian HY, Liu LJ, Zhou BC, Xiao Y, Mao JN, An GY, Rui MZ, Wang T and Zhu CL: Effects of mild hypothermia on the ROS and expression of caspase-3 mRNA and LC3 of hippocampus nerve cells in rats after cardiopulmonary resuscitation. World J Emerg Med. 5:298–305. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Thornberry NA and Lazebnik Y: Caspases: Enemies within. Science. 281:1312–1316. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Wiklund L, Zoerner F, Semenas E, Miclescu A, Basu S and Sharma HS: Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest. Acta Anaesth Scand. 57:1073–1082. 2013. View Article : Google Scholar : PubMed/NCBI |
