Hypothermia In Rats Research Articles

Ammonium chloride-induced hypothermia is attenuated by transient receptor potential channel vanilloid-1, but augmented by ankyrin-1 in rodents

AimsSystemic administration of ammonium chloride (NH4Cl), an acidifying agent used in human patients and experimental conditions, causes hypothermia in mice, however, the mechanisms of the thermoregulatory response to NH4Cl and whether it develops in other species remained unknown. Main methodsWe studied body temperature (Tb) changes in rats and mice induced by intraperitoneal administration of NH4Cl after blockade of transient receptor potential vanilloid-1 (TRPV1) or ankyrin-1 (TRPA1) channels. Key findingsIn rats, NH4Cl decreased Tb by 0.4–0.8°C (p < 0.05). The NH4Cl-induced hypothermia also developed in Trpv1 knockout (Trpv1−/−) and wild-type (Trpv1+/+) mice, however, the Tb drop was exaggerated in Trpv1−/− mice compared to Trpv1+/+ controls with maximal decreases of 4.0 vs. 2.1°C, respectively (p < 0.05). Pharmacological blockade of TRPV1 channels with AMG 517 augmented the hypothermic response to NH4Cl in genetically unmodified mice and rats (p < 0.05 for both). In contrast, when NH4Cl was infused to mice genetically lacking the TRPA1 channel, the hypothermic response was significantly attenuated compared to wild-type controls with maximal mean Tb difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH4Cl-induced Tb drop with a maximal difference of 0.7°C between the pretreatment groups (p = 0.003). SignificanceTRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH4Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular Tb control and careful consideration of NH4Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.

Ginseng extracts improve circadian clock gene expression and reduce inflammation directly and indirectly through gut microbiota and PI3K signaling pathway

Despite the potential benefits of herbal medicines for therapeutic application in preventing and treating various metabolic disorders, the mechanisms of action were understood incompletely. Ginseng (Panax ginseng), a commonly employed plant as a dietary supplement, has been reported to play its hot property in increasing body temperature and improving gut health. However, a comprehensive understanding of the mechanisms by which ginseng regulates body temperature and gut health is still incomplete. This paper illustrates that intermittent supplementation with ginseng extracts improved body temperature rhythm and suppressed inflammatory responses in peripheral metabolic organs of propylthiouracil (PTU)-induced hypothermic rats. These effects were associated with changes in gut hormone secretion and the microbiota profile. The in-vitro studies in ICE-6 cells indicate that ginseng extracts can not only act directly on the cell to regulate the genes related to circadian clock and inflammation, but also may function through the gut microbiota and their byproducts such as lipopolysaccharide. Furthermore, administration of PI3K inhibitor blocked ginseng or microbiota-induced gene expression related with circadian clock and inflammation in vitro. These findings demonstrate that the hot property of ginseng may be mediated by improving circadian clock and suppressing inflammation directly or indirectly through the gut microbiota and PI3K-AKT signaling pathways.

Role of the heat shock protein family in chlorpromazine-induced cardiotoxicity.

Chlorpromazine (CPZ), a first-generation antipsychotic, is widely used in treating schizophrenia and other psychiatric disorders. However, CPZ is also associated with an increased likelihood of sudden cardiac death, and the underlying mechanisms remain unclear. In our study, we aimed to determine the CPZ-induced changes in some members of the heat shock protein family in rat hearts and further explore the possible mechanisms of CPZ-induced cardiotoxicity. Twenty-four Sprague Dawley rats were randomly divided into three groups (n = 8 per group): control, low dose (33.216 mg/kg) and high dose (94.211 mg/kg). CPZ administration induced hypothermia in rats. Pathological changes, including ischaemia and hypoxia, were observed in rat hearts. Furthermore, the serum levels of cardiac Troponin T (c-TN-T) and brain natriuretic peptide (BNP) were elevated in the CPZ-exposed groups. Meanwhile, the protein and gene expression of HSP70, HSP60, HSP27 and HSP10 significantly differed between the CPZ-exposed and control groups. We conclude that acute CPZ exposure could lead to myocardial injury in rats, in which HSPs might play a crucial role. Further investigations are required to elucidate the underlying mechanisms.

Comparative analysis of the effect of diclofenac sodium and etoricoxib on energy metabolism in rat liver in the acute general cooling model

When the ambient temperature decreases, physiological mechanisms that prevent heat loss are activated. However, under cold stress hypothermia develops, which significantly disrupts the functioning of the body and can be transformed into life-threatening. Preventive use of nonsteroidal anti-inflammatory drugs, especially diclofenac sodium and etoricoxib, has been found to reduce the severity of cold trauma. Given that their frigoprotective effect can accompany the impact on the synthesis of eicosanoids when exposed to low temperatures, it is advisable to study mechanisms for preventing hypothermia independent of cyclooxygenase, particularly the influence on energy metabolism. The aim of the study was to figure out the effect of diclofenac sodium and etoricoxib on the indicators of energy metabolism in the liver of rats after acute general cooling. Experiments were carried out on 28 sexually mature male rats, which were given diclofenac sodium (7 mg/kg), etoricoxib (5 mg/kg), or solvent 30 minutes before cold trauma intragastrically (in the intact control and pathology control groups). Acute hypothermia was caused by exposure of animals for 2 hours at a temperature of -18°C. Rectal temperature was measured before and after acute general cooling. The content of lactate, pyruvate and adenosine triphosphate in the liver was measured and the lactate/pyruvate ratio was calculated. Diclofenac sodium, unlike etoricoxib, was found to significantly reduce the severity of hypothermia. Both nonsteroidal anti-inflammatory drugs prevent energy metabolism disorders caused by exposure to cold, namely, reducing the concentration of lactic acid and the ratio of lactate/pyruvate, increasing the content of pyruvate and adenosine triphosphate in the liver of animals. Etoricoxib normalizes the content of energy metabolism intermediates to their levels in intact animals. Diclofenac sodium has a similar effect, the expression of which is inferior to the selective cyclooxygenase-2 inhibitor. Therefore, when administered prophylactically before acute general cooling, diclofenac sodium effectively prevents hypothermia in rats, surpassing etoricoxib. Etoricoxib completely prevents a decrease in the content of pyruvate and adenosine triphosphate, as well as the accumulation of lactic acid in the liver. Diclofenac sodium is inferior to etoricoxib in its effect on energy metabolism, which indicates other mechanisms of frigoprotective action of a non-selective cyclooxygenase inhibitor. The frigoprotective and energotropic properties of nonsteroidal anti-inflammatory drugs dissociate.

Rno-miR-203a-3p and Mex3B contribute to cell survival of iliopsoas muscle via the Socs3-Casp3 axis under severe hypothermia in rats

Forensic diagnosis of fatal hypothermia is considered difficult because no specific findings, such as molecular markers, have been identified. Therefore, determining the molecular mechanism in hypothermia and identifying novel molecular markers to assist in diagnosing fatal hypothermia are important. This study aimed to investigate microRNA (miRNA) and mRNA expression in iliopsoas muscle, which plays a role in homeostasis in mammals, to resolve the molecular mechanism in hypothermia. We generated rat models of mild, moderate, and severe hypothermia, then performed body temperature-dependent miRNA and mRNA expression analysis of the iliopsoas muscle using microarray and next-generation sequencing. Analysis showed that rno-miR-203a-3p expression was lower with decreasing body temperature, while Socs3 expression was significantly increased only by severe hypothermia. Luciferase reporter assays suggested that Socs3 expression is regulated by rno-miR-203a-3p. Socs3 and Mex3B small interfering RNA-mediated knockdown showed that suppressing Mex3B could induce the activation of Socs3, followed by a change in caspase 3/7 activity and adenosine triphosphate levels in iliopsoas muscle cells. These findings indicate that rno-miR-203a-3p and Mex3B are deactivated by a decrease in body temperature, whereby it contributes to suppressing apoptosis by accelerating Socs3. Accordingly, the rno-miR-203a-3p-Socs3-Casp3 or Mex3B-Socs3-Casp3 axis may be the part of the biological defense response to maintain homeostasis under extreme hypothermia.

Mild hypothermia in rat with acute myocardial ischaemia-reperfusion injury complicating severe sepsis.

Myocardial ischemia‐reperfusion injury (MIRI) with concurrent severe sepsis has led to substantial mortality. Mild hypothermia (MHT) has been proved to have a therapeutic effect in either MIRI or severe sepsis, which suggests it might be beneficial for MIRI complicating severe sepsis. In this study, Sprague‐Dawley rats with MIRI complicating severe sepsis were allotted in either MHT (33 ± 0.5°C) group or normothermia (NT, 37 ± 0.5°C) group; as control, rats receiving sham surgery and normal saline were kept at NT. After 2h of temperature maintenance, blood and heart tissue were acquired for detections. Lactate dehydrogenase (LDH) and MB isoenzyme of creatine kinase (CK‐MB) in blood, triphenyl tetrazolium chloride and Evans blue staining, hematoxylin and eosin staining for myocardium were employed to detect myocardial damage. Tumor necrosis factor (TNF)‐α and caspase‐3 was performed by immunohistochemistry to exam myocardial inflammation and apoptosis. Detection of NADPH oxidase (NOX) 2 was for myocardial oxidative stress. In MHT group, systolic blood pressure was improved significantly compared with NT group. Myocardial infarct size, morphological change, LDH and CK‐MB levels were attenuated compared to NT group. Moreover, less expressions of TNF‐α, caspase‐3 and NOX2 in MHT group were presented compared with NT group. MHT showed cardioprotection by improving cardiac dysfunction, reducing myocardial infarct size and attenuating myocardial injury, inflammation, apoptosis and oxidative stress.

Successful induction of deep hypothermia by isoflurane anesthesia and cooling in a non-hibernator, the rat

The aim of the present study was to establish a novel method for inducing deep hypothermia in rats. Cooling rats anesthetized with isoflurane caused a time-dependent decrease in rectal temperature, but cardiac arrest occurred before their body temperature reached 20 °C when isoflurane inhalation was continued during the cooling process. Stopping inhalation of isoflurane when the rectal temperature reached 22.5 °C successfully induced deep hypothermia, although stopping the inhalation at 27.5 °C resulted in spontaneous recovery of rectal temperature. The hypothermic condition was able to be maintained for up to 6 h. A large number of c-Fos-positive cells were detected in the hypothalamus during hypothermia. Both the maintenance of and recovery from hypothermia caused organ injury, but the damage was transient and recovered within 1 week. These findings indicate that the established procedure is appropriate for inducing deep hypothermia without accompanying serious organ injury in rats.

Aqueous extracts of Aconite promote thermogenesis in rats with hypothermia via regulating gut microbiota and bile acid metabolism

BackgroundIntermittent or prolonged exposure to severe cold stress disturbs energy homeostasis and can lead to hypothermia, heart failure, Alzheimer’s disease, and so on. As the typical “hot” traditional Chinese medicine, Aconite has been widely used to treat cold-associated diseases for thousands of years, but its critical mechanisms for the promotion of thermogenesis are not fully resolved. Gut microbiota and its metabolites play a crucial role in maintaining energy homeostasis. Here, we investigated whether the aqueous extracts of Aconite (AA) can enhance thermogenesis through modulation of the composition and metabolism of gut microbiota in hypothermic rats.MethodsThe therapeutic effects of AA on body temperature, energy intake, and the histopathology of white adipose tissue and brown adipose tissue of hypothermic rats were assessed. Microbiota analysis based on 16 S rRNA and targeted metabolomics for bile acids (BAs) were used to evaluate the composition of gut microbiota and BAs pool. The antibiotic cocktail treatment was adopted to further confirm the relationship between the gut microbiota and the thermogenesis-promoting effects of AA.ResultsOur results showed a sharp drop in rectal temperature and body surface temperature in hypothermic rats. Administration of AA can significantly increase core body temperature, surface body temperature, energy intake, browning of white adipose tissue, and thermogenesis of brown adipose tissue. Importantly, these ameliorative effects of AA were accompanied by the shift of the disturbed composition of gut microbiota toward a healthier profile and the increased levels of BAs. In addition, the depletion of gut microbiota and the reduction of BAs caused by antibiotic cocktails reduced the thermogenesis-promoting effect of AA.ConclusionsOur results demonstrated that AA promoted thermogenesis in rats with hypothermia via regulating gut microbiota and BAs metabolism. Our findings can also provide a novel solution for the treatment of thermogenesis-associated diseases such as rheumatoid arthritis, obesity, and type 2 diabetes.

Histopathological, histochemical and biochemical postmortem changes in induced fatal hypothermia in rats

Reaching a postmortem diagnosis of hypothermia is challenging in forensic practice. Therefore, this study was conducted to detect the histopathological, histochemical and biochemical changes that occur in adult albino rats following exposure to induced fatal hypothermia. Twenty-four adult albino rats were divided into the negative control, moderate hypothermia, severe hypothermia and hypoxia groups. Rats in the control group were euthanized when those in the moderate hypothermic group died. Blood samples were collected via heart puncture, and the cerebrum, heart, suprarenal gland, kidney, liver and skeletal muscle were removed to investigate the biochemical, histochemical and histopathological changes. Postmortem assessment depicted significant changes in lipid peroxidation, represented by increased malondialdehyde levels in the studied organs of the rats in hypothermic and hypoxia groups. Histopathological examination of the rats’ organs revealed degeneration and necrosis in the hypothermia and hypoxia groups. Sections taken from the severe hypothermic rats revealed a loss of normal cardiac tissue architecture, necrotic changes in the pyramidal cells in the cerebral cortex, and massive necrosis, mainly in the tubules of the renal cortex and medulla. These findings suggest that histological changes might be used as biochemical markers for postmortem diagnosing of fatal hypothermia, particularly in severe hypothermic conditions. Key points Death by hypothermia is a serious public health problem worldwide. Confirming a diagnosis and determining the cause of death in cases of hypothermia are among the most difficult practices in forensic medicine. Death by hypothermia might be associated with structural abnormalities in various organs. Studies using different tissue staining techniques will enable an overall illustration of the role of histopathological changes in body organs as indicators of hypothermia.

Pre-warming before general anesthesia with isoflurane delays the onset of hypothermia in rats.

General anesthesia causes hypothermia by impairing normal thermoregulatory mechanisms. When using inhalational anesthetic agents, Redistribution of warm blood from the core to the periphery is the primary mechanism in the development of hypothermia and begins following induction of anesthesia. Raising skin temperature before anesthesia reduces the temperature gradient between core and periphery, decreasing the transfer of heat. This prospective, crossover study (n = 17 adult male and female SD rats) compared three treatment groups: PW1% (pre-warming to increase core temperature 1% over baseline), PW40 (pre-warming to increase core temperature to 40°C) and NW (no warming). The PW1% group was completed first to ensure tolerance of pre-warming. Treatment order was then randomized and alternated after a washout period. Once target temperature was achieved, anesthesia was induced and maintained with isoflurane in oxygen without further external temperature support. Pre-warming was effective at delaying the onset of hypothermia, with a significant difference between PW1% (12.4 minutes) and PW40 (19.3 minutes, p = 0.0044 (95%CI -12 to -2.2), PW40 and NW (7.1 minutes, p < 0.0001 (95%CI 8.1 to 16.0) and PW1% and NW (p = 0.003, 95%CI 1.8 to 8.7). The rate of heat loss in the pre-warmed groups exceed that of the NW group: PW1% versus NW (p = 0.005, 95%CI 0.004 to 0.027), PW40 versus NW (p < 0.0001, 95%CI 0.014 to 0.036) and PW1% versus PW40 (p = 0.07, 95%CI -0.021 to 0.00066). Pre-warming alone confers a protective effect against hypothermia during volatile anesthesia; however, longer duration procedures would require additional heating support.

Cardioprotective eff ect of cardiophilic and phytochol preparations under experimental hypothermia hypothermia in rats

At present, diseases of the cardiovascular system in small animals range from 15 to 18%. The most common cause of cardiovascular disease in animals is a decrease in myocardial contractile properties. The results of experimental research to study the effi cacy of «Cardiophil» and «Phytochol» for heart disease in rats are presented. Histological examinations prove that cardiac myocytes are killed by ischemia, with subsequent replacement of connective tissue. As a result, not only the damaged area but also a healthy myocardium is involved in the process of cardiac tissue remodeling. Irreversible damage to cardiomyocytes and vascular structures leads to impaired cardiac function, heart failure and the development of arrhythmias. It is established that the use of drugs «Cardiophil» and «Phytochol» promotes the prevention of the above changes, i.e. prevents cardiovascular diseases, in particular myocardium in animals. For the purpose of experimental studies, a control and experimental group of rats 12 months of age and weighing 220g of 5 animals each were formed. All animals were in the same feeding and keeping conditions. The rats of the study group were individually internally given phytopreparations «Cardiophil» 30 min before feeding at a dose of 5 drops, and in an hour «Phytochol» with a small amount of water 3 times a day for 90 days. At day 91 of the experiment, hypothermia was induced in animals as a stress factor, according to the indicated method. Throughout the study, rats were monitored, taking into account the general condition, behavior, response to external stimuli, and the condition of the hair. After 12-14 hours of fasting for 91 days, the animals were removed from the experiment by the conventional method (gas anesthesia). Material was selected and histological examination was performed according to the indicated method. During the whole period of the experimental studies, no deviations from the norm were found in the rats of the control and experimental group: general condition, behavior, rats were mobile, active, adequately responded to external stimuli, readily received feed, and the hair was clean and dry. The histological changes established, in our opinion, may refl ect diff erent phases of the functional activity of the heart, as well as structural alterations and metabolic phenomena that occurred in the tissues of the myocardium and the valve apparatus of rats under the action of a stress factor – a hypothermic state. Experimental studies have shown that the use of phytopreparations «Cardiophil» and «Phytochol» for preventive purposes positively aff ects the function of the cardiovascular system, in particular myocardium, which indicates their cardioprotective eff ect, and accordingly prevent cardiovascular diseases of animals. Key words: cardiovascular diseases, stress, cardioprotective eff ect, myocardium, hypothermia, Cardiophil, Phytochol, rats.

The Effect of Hypothermia on Some Structural and Functional Characteristics of Lactate Dehydrogenase of the Rat Brain

Abstract—We studied the activity and some physicochemical parameters of LDH in the rat brain under normal and hypothermic conditions. It was found that during hypothermia the activity of LDH in the rat brain increases, while this increase is less pronounced in an enzyme preparation purified from ballast proteins. A study of LDH self-fluorescence showed a decrease in the intensity of total fluorescence of LDH, in which the main contribution is made by tryptophan residues. Analysis of the second derivatives of the fluorescence spectra showed that hypothermia affects tryptophanyls, which are located on the periphery of the LDH molecule. Study of the binding kinetics of the fluorescent probe ANS with LDH showed the presence of at least two types of binding sites of the probe, which differ in polarity. Hypothermia leads to a decrease in the fluorescence intensity of the ANS, a decrease in the number of binding sites, an increase in the probe dissociation constants, and a shift in the inflection position on the graph of the temperature dependence of the ANS fluorescence to higher temperatures. The study of the content of sulfhydryl and carbonyl groups in the LDH molecule suggests that one of the causes of the changes in the activity and spectral characteristics of LDH in the brain of hypothermic rats is the modification of the enzyme by reactive oxygen species.

Vapor inhalation of cannabidiol (CBD) in rats

RationaleCannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. ObjectiveTo further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. MethodsBlood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. ResultsVapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. ConclusionsThe vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.

Condition of microcirculatory and hemostasis systems in rats after moderate hypothermia

Hypothermia produces a generalized impact on an organism, with involvement of all organs and systems into the response. It was shown that hypothermia promotes multi-organ dysfunction syndrome, which makes it important to study the influence of hypothermia on condition of hemostasis and microcirculatory systems.&#x0D; Aim. To study the condition of the hemostasis system and the microcirculatory bed in different periods of moderate hypothermia in rats.&#x0D; Materials and Methods. The current study was performed on 50 male Wistar rats. Condition of microcirculatory blood stream in all animals was assessed with laser Doppler flowmetry. Condition of hemostasis system was studied according to routine protocols and an integrated method of examination – thromboelastography. Statistical analysis was performed using Statistica 6.0 software package (StatSoft, USA) with calculation of Mann-Whitney nonparametric test.&#x0D; Results. Analysis of the experimental data showed that moderate hypothermia produced a pronounced modulating influence on the microcirculatory system. Vasodilatation occurred immediately after reaching the stage of hypothermia, suggesting the beginning of decompensation in the experimental animals. The highest risk for hemodynamic pathologies was observed 5 days after cessation of cooling and was characterized by a massive reduction in the vascular tone, intensification of hemodynamics against the background appearance of thrombinemia markers in the blood stream and pronounced inhibition of fibrinolysis. Enhanced hemodynamics of the nutritional vascular bed with the underlying progressive prothrombotic condition is a potent risk factor for thrombosis and multiple organ dysfunction syndrome. Vasospasm that developed 2 weeks after recovery of the body temperature, indicated a profound modulation of vasculature and preservation of high-level sympathetic input, as well as increasing rigidity of blood vessel walls. Rising fibrinogen concentrations confirm a progressive inflammatory reaction.&#x0D; Conclusion. A moderate degree of hypothermia produces a pronounced modulating effect on the microcirculation. The established regularities make it possible to form a clear understanding of the course and development of the pathological reaction in the body of victims and to give recommendations on the use of pharmacological medicine for preventive therapy. Thus, a period has been established when thrombotic readiness is maximal, and use of anticoagulant and antiplatelet drugs is required, together with drugs that improve rheological properties of blood.

The Effect of Prophylactic Hypothermia on Neurophysiological and Functional Measures in the Setting of Iatrogenic Spinal Cord Impact Injury

Iatrogenic spinal cord injury (iSCI) during spinal corrective surgery can result in devastating complications, such as paraplegia or paraparesis. Perioperatively, iSCI often occurs as a direct injury during spinal cord instrumentation placement. Currently, treatment of iSCI remains limited to posttraumatic hypothermia, which has demonstrated some value in recent clinical trials. Here we report the outcomes of preinjury hypothermia initiated preprocedurally and maintained for a considerable time after iSCI. Twenty-six female Sprague-Dawley rats were assigned at random to either a normothermic group (36 °C) or a hypothermic group (32 °C) and then underwent a laminectomy procedure at the T8 level. Each group was further divided at random to receive a 200-kdyn force contusive spinal cord injury or a sham impact. Hypothermic rats were then rewarmed after 2 hours of hypothermic treatment. Behavioral scores, temperature profiles, weights, and somatosensory evoked potentials were obtained at baseline and at specified time points after the procedure. The median survival was 42 days for the iSCI hypothermic group and 11 days for the iSCI normothermic group (hazard ratio, 3.82; 95% confidence interval, 1.52-9.57). The probability of survival was significantly higher in the iSCI hypothermic group compared with the iSCI normothermic group (χ2= 4.18; P= 0.040). The hypothermic group exhibited a higher Basso, Beattie and Bresnahan (BBB) locomotor rating scale score (17 vs. 14; P < 0.01), lower normalized latencies (1.06 ± 0.16 seconds vs. 1.34 ± 0.17 seconds; P= 0.04), and higher peak-to-peak amplitudes (0.32 ± 0.10 μV vs. 0.12 ± 0.09 μV; P= 0.005). The use of prophylactic hypothermia before iSCI was significantly associated with an increased survival rate, higher BBB scores, and improved neurophysiological measures.

Isoflurane‐Induced Hypothermia Does Not Aggravate Memory Impairment in A Sporadic Alzheimer's Disease Rat Model Produced by Intracerebroventricular Streptozotocin

Several studies have shown that hypothermia and anesthesia are risk factors for Alzheimer's disease. Most of them were performed on healthy elderly rodents. However, the effect of anesthesia‐induced hypothermia in memory in a sporadic Alzheimer's disease animal model has never been studied. In this study, Wistar rats (3‐month‐old) were induced to anesthesia with 3% isoflurane and maintained with 1.5–2% isoflurane in 100% oxygen for 3 hours. In the first 30 min of anesthesia, rats were subjected to a single bilateral intracerebroventricular injection of streptozotocin (STZ, 1 mg/kg) to produce the sporadic Alzheimer's disease model, or its vehicle (0.05 mol/L citrate buffer, pH 4.5, 2 μL/ventricle). The rats were either subjected to hypothermia or not, induced by isoflurane (hypothermic and normothermic groups, respectively). In this sense, during anesthesia, normothermic rats were kept on a heating pad, and their rectal temperature was maintained at 37.5 ± 0.5°C. Hypothermic rats were kept without a heating pad. Spatial working memory was evaluated using Morris Water Maze from the 3rd to 28th‐day postsurgery, and by Y‐maze test on the 30th‐day postsurgery. Recognition memory was evaluated on the 31st‐day postsurgery using the Novel Object Recognition Test. All the procedures were approved by and are in accordance with the local ethics committee from St Joseph's Hospital and Medical Center (protocol n° 485). In the Morris water maze test, both hypothermic and normothermic STZ‐injected rats shown similar impairment in spatial working memory compared to their respective controls, i.e., hypothermic and normothermic vehicle‐injected rats, respectively. In the Y‐maze test, normothermic STZ‐injected rats shown a deficit in spatial working memory compared to normothermic vehicle‐injected rats (p = 0.028). However, this effect was missed in hypothermic groups with no difference between STZ‐ and vehicleinjected groups (p = 0.073). Similarly, in the Novel Object Recognition Test, recognition memory was impaired in normothermic STZ‐injected rats compared to normothermic vehicleinjected rats (p = 0.012) and no effect was observed between hypothermic STZ‐ and vehicleinject rats (p = 0.118). In conclusion, isoflurane‐induced hypothermia does not aggravate the STZ‐deleterious effect in recognition memory and spacial work memory in rats.Support or Funding InformationThis work was supported by the Brazilian National Council for Scientific and Technological Development (grant 449102/2014‐9 to D.C.C.) and the São Paulo Research Foundation (grants 2015/02991‐0 to M.C.A., 2015/23426‐9 to D.C.C., and 2016/01836‐3 to R.C.L.V.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats

AimsTo initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor. Materials and methodsWe have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle. Key findingsAfter a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C–23 °C. The hypothermic state may continue on average for 16–17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4–8 days later they were restored. SignificanceSuspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds' pharmacological profiles, invivo targets, thermoeffectors recruited and implications for drug development.

AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

Trace amine-associated receptor 1 agonists RO5263397 and RO5166017 attenuate quinpirole-induced yawning but not hypothermia in rats.

Increasing evidence suggests that trace amine-associated receptor 1 (TAAR1) is an important modulator of the dopaminergic system. Existing molecular evidence indicates that TAAR1 regulates dopamine levels through interactions with dopamine transporters and D2 receptors. However, investigations to date have not been exhaustive and other pathways may be involved. In this study, we used a well-described set of behaviors, quinpirole-induced yawning and hypothermia, to explore the potential interaction of TAAR1 and D3 receptors, which are members of the 'D2-like' dopamine receptor subfamily. Previous studies have shown that for D2/D3 receptor agonists, the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of yawning and induction of hypothermia are D2 receptor-mediated effects. Quinpirole produced an inverted U-shaped dose-effect curve for yawning, which was shifted downward dose-dependently by each of the TAAR1 agonists RO5263397 and RO5166017. Quinpirole also produced dose-dependent hypothermia, which was not affected by either TAAR1 agonist. These results suggest that TAAR1 agonists may interact with D3 receptors and/or its downstream pathways, as opposed to D2 receptors. These findings may shed light on a previously unexplored possibility for the mechanism of TAAR1-mediated effects.

Synthetic cannabinoids found in “spice” products alter body temperature and cardiovascular parameters in conscious male rats

BackgroundThe misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Δ9-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. MethodsBiotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. ResultsTHC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH–018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the α1 adrenergic antagonist prazosin. ConclusionsOur results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow.