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A basic tenet of biology is that body temperature (Tb) has a marked effect on oxygen uptake of resting animals. For most animals, the temperature coefficient (Q10) is >> 2.5; e.g., resting oxygen uptake changes about 11% per degree C change in Tb. An important consequence of this dependence is that hyperthermia could be deleterious for hypoxic animals, particularly for oxygen sensitive organs, e.g., heart and brain. Conversely, a moderate degree of hypothermia could be beneficial during hypoxia. This concept is not new. Forced hypothermia is sometimes used in surgical procedures, particularly for heart and brain surgery. However, in many situations where hypothermia might have benefits, e.g., pediatric intensive care, it is not permitted. This is due in part to dogma and in part to the real and potential disadvantages of hypothermia, even in severely hypoxic animals. Among these in ventricular fibrillation. This is apparently preventable if blood pH is allowed to rise following the "Buffalo Curve." Another important disadvantage, were it to occur, is elevation of oxygen demand due to a thermogenic responses. However, at least in some species, the thermogenic response is blunted during hypoxia; e.g., in young rats. Furthermore, even if a thermogenic response occurs, this takes place primarily in muscles (shivering) and brown fat (non-shivering) and not in the O2-sensitive organs, heart and brain. A third disadvantage, for prolonged hypothermia, might be impairment of the immune response, a serious problem if hypoxia is combined with infection. This paper will review four aspects of behavioral fever and hypothermia: the occurrence among animals, the mechanisms and mediators that might trigger behavioral responses, and the functional significance.
Comp Biochem Physiol B Biochem Mol Biol 1996 Jan
PMID:Hypothermia in hypoxic animals: mechanisms, mediators, and functional significance. 893 41

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.
Mol Chem Neuropathol
PMID:Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia. 897 96

Immediate early genes are induced by transient global ischemia. Using immunohistochemistry we studied the effect of intraischemic hypothermia (30 degrees C) on the expression of c-fos and fos-B proteins following 10 min forebrain ischemia in the gerbil. Postischemia (PI) periods of 1 hour (h), 6 h, 1 day (d) and 2 d and nonischemic controls were examined in normothermic and hypothermic brains. In normothermic ischemic brains, marked expression of c-fos occurred in the dentate gyrus after 1 h PI which extended to CA2-4 regions by 6 h. Hypothermia hastened the time course of c-fos expression as it was expressed simultaneously in the dentate gyrus as well as CA2-4 regions after only 1 h, and by 6 h the expression remained only in the CA2-4 regions and not the dentate gyrus in hypothermic ischemic brains. There was no difference in its expression between normothermic and hypothermic brains in the 1 d and 2 d PI animals. Somewhat similar changes were noted in fos-B expression. In normothermic ischemic brains fos-B was induced in the dentate gyrus by 1 h PI, and by 6 h it extended to involve CA1-4 cells. The hypothermic ischemic brains showed faster induction of fos-B so that the dentate gyrus as well as CA1-4 regions were immunopositive at 1 h PI. There was no difference in its expression between normothermic and hypothermic brains in the subsequent PI periods of 6 h, 1 d and 2 d. The shift towards faster sequential induction of these genes by hypothermia in ischemic brains may be indicative of preservation of or faster recovery of mechanisms involved in intracellular signalling.
Brain Res Mol Brain Res 1996 Dec
PMID:Expression of c-fos and fos-B proteins following transient forebrain ischemia: effect of hypothermia. 901 91

The expression of junD was studied in the rat hippocampus by in situ hybridization after 15 min of normothermic (37 degrees C) and hypothermic (33 degrees C) transient forebrain ischemia. Ischemia was induced by common carotid artery occlusion combined with hypotension leading to damage in the CA1 region of the hippocampus which was prevented by hypothermia. junD mRNA was induced in the hippocampus within 2 h of reperfusion and was strong in the dentate gyrus but weak in the CA3 and CA1 subregions. Intraischemic hypothermia significantly augmented the junD induction in the dentate gyrus. During late reperfusion (between 12 and 36 h after ischemia) a transient increase in junD mRNA was seen in the normothermic CA3 which was abolished in the hypothermic brains. In contrast, in the normothermic CA1 a continuous increase of junD was seen. This was significantly reduced by intraischemic hypothermia. We suggest that the early induction in junD expression in the dentate gyrus and in the hypothermic CA3 region is a protective reaction to the ischemic stress. The marked increase in resistant brain areas could be due to the preserved intracellular signaling pathways and a subsequent maintenance of protein synthesis. The late continuous increase, unique to the vulnerable normothermic CA1 region, suggests that junD participates in a transcriptional process that may be important for delayed neuronal death in the hippocampus following transient forebrain ischemia.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Induction of junD mRNA after transient forebrain ischemia in the rat. Effect of hypothermia. 903 18

In the present study we examined the impact of glycolysis and glucose oxidation on myocardial calcium control and mechanical function of fatty acid-perfused rat hearts subjected to hypothermia rewarming. One group (control) was given glucose (11.1 mM) and palmitate (1.2 mM) as energy substrates. In a second group glycolysis was inhibited by iodoacetate (IAA, 100 microM) and replacement of glucose with pyruvate (5 mM), whereas in the third group glucose oxidation was stimulated by administration of dichloroacetate (DCA, 1 mM) and insulin (500 microU/ml). All groups showed a rise in myocardial calcium ([Ca]total in response to hypothermia (10 degrees C). However, [Ca]total was significantly lower both in IAA- and DCA-treated hearts, as compared to controls (2.20 +/- 0.22 and 2.94 +/- 0.20 v 3.83 +/- 0.29 nmol/mg dry wt., P < 0.025). The reduced calcium load in the treated hearts was correlated with higher levels of high energy phosphates. Following rewarming control and DCA-treated hearts still showed elevated [Ca]total, whereas IAA-treated hearts [Ca]total was not different from the pre-hypothermic value. All groups showed a reduction in cardiac output following rewarming. Furthermore, the control group, in contrast to both IAA- and DCA-treated hearts, showed a significant reduction in systolic pressure. These results show that hypothermia-induced calcium uptake in glucose and fatty acid-perfused rat hearts was reduced by two different metabolic approaches: (1) inhibition of glycolysis by IAA while simultaneously by-passing the glycolytic pathway by exogenous pyruvate: and (2) stimulation of glucose oxidation by DCA. Thus, glycolytic ATP is not an essential regulator of sarcolemmal calcium transport under the present experimental conditions. Instead, we suggest that a change in oxidative substrate utilization in favour of carbohydrates may improve myocardial calcium homeostasis during hypothermia and rewarming.
J Mol Cell Cardiol 1997 Feb
PMID:Stimulation of carbohydrate metabolism reduces hypothermia-induced calcium load in fatty acid-perfused rat hearts. 914 Aug 12

Cardiac surgery is usually performed under conditions of cardioplegic ischemic arrest. To protect the heart during the ischemic period, the myocardium is exposed to varying degrees of hypothermia. Although hyperthermia is known to induce the heat shock response, the molecular effects of hypothermia on the myocardium have not been investigated. We have studied the effect of hypothermia on the induction of heat shock proteins in primary cultures of neonatal cardiomyocytes. Cold stress in cardiomyocytes induced a 6 fold increase in the heat shock protein HSP70 as compared to control. Increased HSP70 protein levels correlated with induction of HSP70 mRNAs. Maximal levels of HSP70 protein appeared 4-6 h following recovery from cold shock, indicating the transient nature of the response. Induction of HSP25 mRNA was also observed in cold-shocked cardiomyocytes, even though increased HSP25 protein levels were not detected. Our results indicate that hypothermia is capable of inducing the heat shock response in neonatal cardiomyocytes.
Mol Cell Biochem 1997 Aug
PMID:Characterization of cold-induced heat shock protein expression in neonatal rat cardiomyocytes. 927 66

The use of hypothermia to mitigate cerebral ischemic injury is not new. From early studies, it has been clear that cooling is remarkably neuroprotective when applied during global or focal ischemia. In contrast, the value of postischemic cooling is typically viewed with skepticism because of early clinical difficulties and conflicting animal data. However, more recent rodent experiments have shown that a protracted reduction in temperature of only a few degrees Celsius can provide sustained behavioral and histological neuroprotection. Conversely, brief or very mild hypothermia may only delay neuronal damage. Accordingly, protracted hypothermia of 32-34 degrees C may be beneficial following acute clinical stroke. A thorough mechanistic understanding of postischemic hypothermia would lead to a more selective and effective therapy. Unfortunately, few studies have investigated the mechanisms by which postischemic cooling conveys its beneficial effect. The purpose of this article is to evaluate critically the effects of postischemic temperature changes with a comparison to some current drug therapies. This article will stimulate new research into the mechanisms of lengthy postischemic hypothermia and its potential as a therapy for stroke patients.
Mol Neurobiol 1997 Jun
PMID:Postischemic hypothermia. A critical appraisal with implications for clinical treatment. 929 62

Perinatal asphyxia (PA) produces changes in nitric oxide synthase (NOS) activity in neuronal and endothelial cells of the striatum and neocortex. The changes were examined using a histochemical NADPH-diaphorase (NADPH-d) staining method. Newborn rats were exposed to severe PA at 37 degrees C and other groups were subjected to severe PA under hypothermic condition (15 degrees C) for 20 or 100 min, respectively. Quantitative image analysis was performed on the striatum and neocortex in order to count cell number of reactive neurons and to compare the pattern of staining between the different groups of animals. Severe asphyctic pups showed an important neuronal loss in striatum and neocortex that was reduced by hypothermia. NADPH-d(+) neurons with reactive processes were found in the lateral zone of the striatum and neocortex in asphyctic pups. Controls and hypothermic striatum showed rounded cells without reactive process, while no cells were stained in cortex. There was also an increase in NADPH-d activity in endothelial cells in severe asphyctic pups in striatum and neocortex vs control and hypothermically treated animals. Our data evidenced that an inappropriate activation of NOS in neuronal and endothelial cells induced by PA is related to neuronal injury. Hypothermia inhibits neuronal injury and may be a valuable neuroprotective agent.
Mol Chem Neuropathol 1997 Aug
PMID:Short-term changes in NADPH-diaphorase reactivity in rat brain following perinatal asphyxia. Neuroprotective effects of cold treatment. 933 71

The aim of this study was to evaluate the additive protective efficiency of ischemic preconditioning when used in combination with conventional clinically relevant cardioprotective methods of hypothermia or hypothermic cardioplegia during sustained global ischemia. Isolated rat hearts were aorta-perfused with Krebs-Henseleit buffer and were divided into six groups (n = 10 each). Group I: Ischemia at 34 degrees C for 60 min; Group PC + I: preconditioned (PC) ischemia at 34 degrees C, 2 episodes of 5 min ischemia and 10 min reperfusion at 34 degrees C followed by I; Group HI: hypothermic ischemia at 10 degrees C for 60 min; Group PC + HI: preconditioned (PC) hypothermic ischemia, 2 episodes of 5 min ischemia and 10 min reperfusion at 34 degrees C followed by HI; Group CPL + HI: single dose of 'Plegisol' cardioplegia followed by HI; Group PC + CPL + HI: preconditioned hypothermic cardioplegia, followed by CPL + HI. At the end of 60 min ischemia, all the hearts were reperfused at 34 degrees C for 30 min when post-ischemic recovery in left ventricular contractile function and coronary vascular dynamics was computed and compared. There was a significant depression in the post-ischemic recovery of developed pressure (Pmax), positive derivative of pressure (+dp/dt), negative derivative of pressure (-dp/dt) and heterometric autoregulation (HA) of contractile force in all the groups, with no major differences between the groups. Left ventricular end-diastolic pressure (LVEDP) was significantly elevated after I at 34 degrees C. Preconditioning (PC + I) prevented the rise in the LVEDP and this was accompanied by a significant reduction in the release of purine metabolites in the coronary effluents, particularly adenosine, during the immediate reperfusion period. Hypothermia (HI) provided essentially the same level of metabolic and mechanical preservation as offered by PC + I. Combination of hypothermia with preconditioning (PC + HI) or cardioplegia (PC + CPL + HI), did not further enhance the preservation. Post-ischemic recovery in the regional contractile function (segment shortening, %SS) followed nearly identical pattern to global (Pmax) recovery. Post-ischemic recovery in coronary flow (CF) was significantly reduced and coronary vascular resistance (CVR) was significantly increased in all the groups. Myogenic autoregulation (transient and sustained) was generally enhanced indicating increased vascular reactivity. Preconditioning did not alter the time-course of these changes. Preconditioned ischemia (34 degrees C) preserved left ventricular diastolic functions and prevented the contracture development after sustained ischemia reperfusion at 34 degrees C. This protective effect of preconditioning was possibly mediated by the reduction in the breakdown of purine metabolites. Hypothermia alone or in combination with crystalloid cardioplegia prevented the irreversibility of the ischemic injury but produced contractile and vascular stunning which was not improved by ischemic preconditioning. The results of this study indicate that preconditioning when combined with hypothermia or hypothermic cardioplegia offered no significant additional protection.
Mol Cell Biochem 1997 Nov
PMID:Ischemic preconditioning is not additive to preservation with hypothermia or crystalloid cardioplegia in the globally ischemic rat heart. 940 76

Proliferating cell nuclear antigen (PCNA) is required for completion of the DNA synthesis step of DNA replication as well as nucleotide excision repair (NER) of damaged DNA. We investigated the expression of PCNA mRNA and the levels of PCNA protein in the adult rat hippocampus following normo- and hypothermic global forebrain ischemia. Hypothermia protected the CA1 neurons from ischemic damage. A constitutive expression of PCNA mRNA and protein was detected in all hippocampal subfields, as well as in other brain regions. During reperfusion, PCNA mRNA levels were up-regulated in the vulnerable CA1 subfield at 36 h following normothermic ischemia. In hypothermia, this induction appeared already after 18 h. Following normothermic ischemia, nuclear PCNA immunoreactivity was largely abolished during reperfusion in the vulnerable CA1 neurons, prior to cell death. In contrast, total PCNA protein content of this region, as measured by Western blotting, remained largely unchanged. In the CA3 region, a transient decrease in nuclear PCNA immunoreactivity was observed. In the dentate gyrus region, no down-regulation of nuclear or total PCNA protein was observed during reperfusion. Following hypothermic ischemia, the PCNA protein levels did not decrease in any of the hippocampal subregions. In contrast, no change in the levels of Ref-1, a protein involved in base excision DNA repair (BER), was observed following normo- or hypothermic ischemia. Our findings indicate an altered functional state of PCNA protein in the ischemia-sensitive CA1 neurons suggesting that DNA repair processes are affected in these post-mitotic cells following ischemia. Impaired DNA repair may play a role in the development of postischemic neuronal damage.
Brain Res Mol Brain Res 1998 Oct 01
PMID:Changes in proliferating cell nuclear antigen, a protein involved in DNA repair, in vulnerable hippocampal neurons following global cerebral ischemia. 975 27


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