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Limited Therapeutic Time Windows of Mild-to-Moderate Hypothermia in a Focal Ischemia Model in Rat  [PDF]
Heng Zhao,Gary Steinberg
Stroke Research and Treatment , 2011, DOI: 10.4061/2011/131834
Abstract: Although many studies have shown the great potential of induced hypothermia in stroke treatment, we recognize that there are limitations to the protective effects of hypothermia even in the laboratory. Here, we review our experiments on the protective effects of mild-to-moderate hypothermia in rats. Focal ischemia was induced by bilateral common carotid artery (CCA) occlusion for 1 to 2 hours combined with permanent or transient middle cerebral artery (MCA) occlusion. We compared the effects of mild ( ) and moderate ( ) hypothermia, evaluated therapeutic time windows, and studied the underlying mechanisms. On review, our findings revealed that the protective effects of induced mild hypothermia ( ) were limited, and the therapeutic time window of even moderate hypothermia ( ) was very short in our specific models, although this limitation might be due to the relatively brief periods of hypothermia used. In addition, we found that hypothermia reduced brain injury by preserving Akt activity, PTEN phosphorylation and εPKC activity, while inhibiting ROS production, and δPKC activity. 1. Introduction One of the gold standards of neuroprotectants against stroke in animal experiments [1, 2] induced mild (33 to 36°C) to moderate (28 to 32°C) hypothermia has been the focus of several clinical trials for the treatment of cerebral ischemia. In the past decade, prospective randomized controlled studies have demonstrated that induced hypothermia improves neurological function in patients suffering cardiac arrest from ventricular fibrillation [3] and reduces risk of death or disability in neonates following hypoxic-ischemic encephalopathy [4, 5]. However, the clinical translation of hypothermia for acute stroke treatment is still in its early stages. Many barriers remain, including onset time, duration, and depth of hypothermia [6]. In the process of extrapolating animal studies to human patients, significant gaps exist even between the design of laboratory experiments and clinical trials. For instance, many previous animal models used complete reperfusion [7–9], while most stroke patients suffer from permanent cerebral artery occlusion [10, 11]. Even with t-PA treatment, slightly less than one third of patients achieve complete reperfusion, one-third achieve partial reperfusion, and in the rest reperfusion is absent [11, 12]. Therefore, the ability to select animal stroke models that properly mimic clinical stroke is a critical step in evaluating the protective effects of induced hypothermia. Our laboratories have studied the protective effects of mild-to-moderate
Mild hypothermia causes differential, time-dependent changes in cytokine expression and gliosis following endothelin-1-induced transient focal cerebral ischemia
An-Ga?lle Ceulemans, Tine Zgavc, Ron Kooijman, Said Hachimi-Idrissi, Sophie Sarre, Yvette Michotte
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-60
Abstract: The Endothelin-1 (Et-1) model was used to elicit a transient focal cerebral ischemia in male Wistar rats. In this model, the core and penumbra of the insult are represented by the striatum and the cortex respectively. We assessed the effects of 2 hours of hypothermia, started 20 minutes after Et-1 injection on neurological outcome and infarct volume. Furthermore, pro- and anti-inflammatory cytokine expression was determined using ELISA. Microgliosis and astrogliosis were investigated using CD-68 and GFAP staining respectively. All parameters were determined 8, 24, 72 hours and 1 week after the administration of Et-1.Et-1 infusion caused neurological deficit and a reproducible infarct size which increased up to 3 days after the insult. Both parameters were significantly reduced by hypothermia. The strongest reduction in infarct volume with hypothermia, at 3 days, corresponded with increased microglial activation. Reducing the brain temperature affected the stroke induced increase in interleukin-1β and tumor necrosis factor α in the striatum, 8 hours after its induction, but not at later time points. Transforming growth factor β increased as a function of time after the Et-1-induced insult and was not influenced by cooling. Hypothermia reduced astrogliosis at 1 and 3 days after stroke onset.The beneficial effects of hypothermia after stroke on infarct volume and functional outcome coincide with a time-dependent modulation of the cytokine expression and gliosis.Stroke is an important cause of morbidity and mortality in industrialized countries and few therapies exist thus far. It is generally acknowledged that many agents, proven neuroprotective in experimental models, fail in clinical practice, possibly because they cannot respond to the complex multifaceted nature of the ischemic cascade after stroke [1-3]. Hypothermia is a well established and robust neuroprotective treatment and has been the focus of research as it may act on several pathways simultaneously [4,5].
Hypothermia Protects the Brain from Transient Global Ischemia/Reperfusion by Attenuating Endoplasmic Reticulum Response-Induced Apoptosis through CHOP  [PDF]
Xiaojie Liu, Mingshan Wang, Huailong Chen, Yunliang Guo, Fuguo Ma, Fei Shi, Yanlin Bi, Ying Li
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053431
Abstract: 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-homolo gous 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.
Mild Hypothermia Attenuates Mitochondrial Oxidative Stress by Protecting Respiratory Enzymes and Upregulating MnSOD in a Pig Model of Cardiac Arrest  [PDF]
Ping Gong, Chun-Sheng Li, Rong Hua, Hong Zhao, Zi-Ren Tang, Xue Mei, Ming-Yue Zhang, Juan Cui
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035313
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.
Delayed minocycline but not delayed mild hypothermia protects against embolic stroke
Chen Wang, Tao Yang, Raza Noor, Ashfaq Shuaib
BMC Neurology , 2002, DOI: 10.1186/1471-2377-2-2
Abstract: Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA). Infarction volume was measured at 48 h after the injury. Mortality was also recorded.Delayed administration of minocycline alone or delayed minocycline plus delayed mild hypothermia reduced the infarction volume significantly. However, delayed mild hypothermia alone was not protective and delayed mild hypothermia in combination with minocycline did not show any additive effect.These results suggest that minocycline is beneficial in focal ischemic brain injury, and the lack of the enhanced neuroprotection may be due to the brief exposure to hypothermia.Inflammatory reactions occur within the brain after ischemic injury and these may contribute to secondary cerebral damage. Because inflammation reactions occur rapidly and persist for at least a few days after ischemic brain injury [2,7,11], these secondary responses are potential targets for human therapy with a sufficiently wide therapeutic window. Minocycline is a semisynthetic second-generation drug of tetracycline group and it exerts anti-inflammatory effects that are completely separate and distinct from its antimicrobial action [12]. Minocycline is used clinically for treatment of severe inflammatory diseases and rheumatoid arthritis [12]. Recent studies have shown that minocycline reduces the loss of hippocampal pyramidal neurons when used in a gerbil model of global ischemia [20]. In a rat model of ischemia induced by occlusion of the middle cerebral artery (MCA) with a suture, minocycline is also an effective neuroprotective agent [21]. Mild hypothermia induced before and after ischemic brain injury reduces the structural, metabolic and behavioral changes due to ischemia [4,14,15]. In global ischemic injury model of repetitive forebrain ischemia, we have demonstrated that mild hypothermia protects neurons from damage [14]. We and other group have also shown that the protective effect of mild hypothermia can
Neuroprotective effect of mild hypothermia in the temporary brain ischemia in cats
Nakano, Hiroshi;Colli, Benedicto Oscar;Lopes, Luiza da Silva;
Arquivos de Neuro-Psiquiatria , 2007, DOI: 10.1590/S0004-282X2007000500015
Abstract: objective: to evaluate the neuroprotective effect of mild hypothermia during temporary focal ischemia in cats. method: 20 cats underwent middle cerebral artery 60 minutes occlusion and 24 hours reperfusion: 10 under normothermia and 10 under mild hypothermia (32o c). brain coronal sections 2mm thick were stained with 2,3,5-triphenyltetrazolium hydrochloride, photographed and evaluated with software for volume calculation. results:cortical ischemia was found in 7 and basal ganglia ischemia in 8 animals of group 1 and in both regions in 5 animals of group 2 (no difference: p=0.6499 for cortical; p=0.3498 for basal ganglia). no ischemia was found in 5 animals of group 2 and in none of group 1 (significant difference, p=0.0325). the infarct volume was greater in group 1 than 2 (p=0.0433). conclusion: mild hypothermia did not interfere with location of ischemia, but it was effective for reducing the infarct volume.
Analysis of the NMDA in Focal Cerebral Ischemia in Rats
Tirapelli,D. P. C; Carlotti Jr,C. G; Leite,J. P; Lizarte,F. S. N; Tirapelli,L. F; Colli,B. O;
International Journal of Morphology , 2012, DOI: 10.4067/S0717-95022012000300035
Abstract: nmdar (n-methyl-d-aspartate receptor) is one subtype of ionotrophic glutamate receptor which is extensively distributed in the central nervous system (cns). in the mammalian cns, nmdar serves prominent roles in the pathophysiologic process of cerebral ischemia. this study aimed to investigate the pattern of expression of protein and gene of the excitatory neurotransmitter nmdar in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. 120 rats were randomly divided into 6 groups (20 animals each): control - no surgery; sham - simulation of surgery; ischemic - focal ischemia for 1 hour, without reperfusion; ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. ten animals from each experimental group were used to establish the volume of infarct. transient focal cerebral ischemia was obtained in rats by occlusion of the middle cerebral artery with an intraluminal suture. the infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the protein and gene nmda were evaluated by immunohistochemistry and quantitative real-time pcr, respectively. increases in the protein and gene nmda receptor in the ischemics areas were observed and these increases were reduced by hypothermia and ketoprofen. the increase in the nmda receptor protein and gene expression observed in the ischemic animals was reduced by neuroprotection (hypothermia and ketoprofen). the nmda receptor increases in the ischemic area suggests that the nmda mediated neuroexcitotoxicity plays an important role in cell death and that the neuroprotective effect of both, hypothermia and ketoprofen is directly involved with the nmda.
Regional mild hypothermia in the protection of the ischemic brain
Prandini, Mirto Nelso;Lacanna, Santino Nunes;Valente, Paulo Roberto;Stavale, Jo?o Norberto;
Acta Cirurgica Brasileira , 2002, DOI: 10.1590/S0102-86502002000400006
Abstract: objective: to demonstrate that mild hypothermia can be a protective element when an ischemic onset occurs in rabbit brains. methods: a rabbit model of focal ischemia was used to test the protection provided by mild hypothermia regionally produced by means of the placement of ice bag on the scalp of a hemicranium which has had previously its bone removed. twenty new zealand white rabbits were divided into two groups as follows: (a) a control group where an ischemic lesion was produced by coagulation of the middle cerebral artery and (b) a brain protected group where mild hypothermia was provided during 80 to 100 minutes after the same ischemic lesion. the brains slices were stained with 2,3,5-triphenyletrazolium (ttc). the sections were photographed with a digital camera and the infarct volume was measured through a computer program. results: the average of infarct volume was 70.53 mm3 in the control group. in the protected group, the average of infarct volume was 41,30 mm3 only in five animals. five animals of this group did not demonstrate macroscopically and microscopically infarct area. conclusions: we concluded that mild hypothermia regionally produced may protect ischemic brains of rabbits.
Regional mild hypothermia in the protection of the ischemic brain  [cached]
Prandini Mirto Nelso,Lacanna Santino Nunes,Valente Paulo Roberto,Stavale Jo?o Norberto
Acta Cirurgica Brasileira , 2002,
Abstract: Objective: To demonstrate that mild hypothermia can be a protective element when an ischemic onset occurs in rabbit brains. Methods: A rabbit model of focal ischemia was used to test the protection provided by mild hypothermia regionally produced by means of the placement of ice bag on the scalp of a hemicranium which has had previously its bone removed. Twenty New Zealand White rabbits were divided into two groups as follows: (A) a control group where an ischemic lesion was produced by coagulation of the middle cerebral artery and (B) a brain protected group where mild hypothermia was provided during 80 to 100 minutes after the same ischemic lesion. The brains slices were stained with 2,3,5-Triphenyletrazolium (TTC). The sections were photographed with a digital camera and the infarct volume was measured through a computer program. Results: The average of infarct volume was 70.53 mm3 in the control group. In the protected group, the average of infarct volume was 41,30 mm3 only in five animals. Five animals of this group did not demonstrate macroscopically and microscopically infarct area. Conclusions: We concluded that mild hypothermia regionally produced may protect ischemic brains of rabbits.
Analysis of the NMDA in Focal Cerebral Ischemia in Rats Análisis del NMDA en Isquemia Cerebral Focal en Ratas
D. P. C Tirapelli,C. G Carlotti Jr,J. P Leite,F. S. N Lizarte
International Journal of Morphology , 2012,
Abstract: NMDAR (N-methyl-D-aspartate receptor) is one subtype of ionotrophic glutamate receptor which is extensively distributed in the central nervous system (CNS). In the mammalian CNS, NMDAR serves prominent roles in the pathophysiologic process of cerebral ischemia. This study aimed to investigate the pattern of expression of protein and gene of the excitatory neurotransmitter NMDAR in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. 120 rats were randomly divided into 6 groups (20 animals each): control - no surgery; sham - simulation of surgery; ischemic - focal ischemia for 1 hour, without reperfusion; ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. Ten animals from each experimental group were used to establish the volume of infarct. Transient focal cerebral ischemia was obtained in rats by occlusion of the middle cerebral artery with an intraluminal suture. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the protein and gene NMDA were evaluated by immunohistochemistry and quantitative real-time PCR, respectively. Increases in the protein and gene NMDA receptor in the ischemics areas were observed and these increases were reduced by hypothermia and ketoprofen. The increase in the NMDA receptor protein and gene expression observed in the ischemic animals was reduced by neuroprotection (hypothermia and ketoprofen). The NMDA receptor increases in the ischemic area suggests that the NMDA mediated neuroexcitotoxicity plays an important role in cell death and that the neuroprotective effect of both, hypothermia and ketoprofen is directly involved with the NMDA. NMDAR (N-metil-D-aspartato) es un tipo de receptor de glutamato ionotrópico y está ampliamente distribuido en el sistema nervioso central (SNC). En el SNC de mamíferos, NMDAR se destaca de manera importante en el proceso fisiopatológico de la isquemia cerebral. Este estudio tuvo como objetivo investigar el patrón de expresión de proteínas y genes para el NMDA neurotransmisor excitatorio experimental de la isquemia cerebral focal y el vacío en la neuroprotección con hipotermia y ketoprofeno. Se dividieron 120 ratas aleatoriamente en grupos de 6 animales cada uno (20): Control - sin cirugía; Sham - simulación de cirugía; isquémicas - isquemia focal durante 1 hora, sin reperfusión isquémica; hipotermia intra-isquémica; isquemia; previa aplicación de ketoprofeno intravenoso, e
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