Hypothermic Action Research Articles

Inhibition of mitochondrial function: An alternative explanation for the antipyretic and hypothermic actions of acetaminophen

AimsAcetaminophen is the medication of choice when treating fever because of its limited anti-inflammatory effects. However at overdose it can cause mitochondrial dysfunction and damage, often associated with metabolism to N-acetyl-p-benzoquinone imine (NAPQI). What has never been investigated is whether the inhibition of mitochondrial function, particularly fatty acid uptake and oxidation could be the key to its antipyretic and hypothermic properties. MethodsMitochondrial function and fatty acid oxidation (FAO) was determined by measuring oxygen consumption rate (OCR) in isolated mitochondria and in 3T3-L1 adipocytes using the XFp Analyser. Basal fatty acids and adrenergic stimulated OCR of mitochondria and 3T3-L1 adipocytes were assessed with acetaminophen and compared to NAPQI, etomoxir, and various mitochondrial stress compounds. Key findingsUsing the XFp Analyser, acetaminophen (10 mM) decreased FAO by 31 % and 29 % in basal and palmitate stimulated adipocytes. NAPQI (50 μM) caused a 63 % decrease in both basal and palmitate stimulated FAO. Acetaminophen (10 mM) caused a 34 % reduction in basal and adrenergic stimulated OCR. In addition acetaminophen also inhibited complex I and II activity at 5 mM. NAPQI was far more potent at reducing mitochondrial respiratory capacity, maximum respiratory rates and ATP production than acetaminophen. SignificanceThese studies demonstrate the direct inhibition of mitochondrial function by acetaminophen at concentrations which have been shown to reduce fever and hypothermia in mammals. Understanding how antipyretics directly affect mitochondrial function and heat generation could lead to the development of new antipyretics which are not compromised by the anti-inflammatory and toxicity of the current medications.

Antioxidant and Hypoglycemic Activity of Sequentially Extracted Fractions from Pingguoli Pear Fermentation Broth and Identification of Bioactive Compounds.

Pear fruits have been reported to contain abundant bioactive compounds and exhibit antidiabetic activity. In this study, Pingguoli pear (Pyrus pyrifolia cv.‘Pingguoli’) fermentation broth was sequentially extracted by five solvents with increasing polarity (petroleum ether, chloroform, ethyl acetate, n-butanol, and water) to evaluate its antioxidant and hypothermic activities, and then the main compounds of the fraction with the highest activity were assessed, which might be responsible for such activities. The results showed that the ethyl acetate fraction (EAF) exhibited the highest antioxidant activity according to DPPH (IC50 = 0.238 mg/mL), ABTS (IC50 = 0.293 mg/mL), and FRAP (IC50 = 0.193 mg/mL) assays. The in vitro hypoglycemic activity assay showed that EAF exhibited the strongest inhibitory effect, with IC50 values of 0.34 and 0.95 mg/mL for α-amylase and α-glucosidase, respectively. The glucose consumption in HepG2 cells treated with EAF was significantly increased to 252%, compare with control group. Liquid chromatography–mass spectrometry analysis implied that the main compounds, 3′-C-glucosylisoliquiritigenin, robustside D, caffeic acid, and chlorogenic acid may be potential candidates for the antioxidant and hypoglycemic activities of the EAF. This study suggested that EAF of Pingguoli pear fermentation broth could be utilized for development of potential functional food and antidiabetic agents.

Substantial impact of 3-iodothyronamine (T1AM) on the regulations of fluorescent thermoprobe-measured cellular temperature and natriuretic peptide expression in cardiomyocytes

There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone metabolite, that induces negative inotropic and chronotropic actions in the heart and exerts systemic hypothermic action. We explored the direct impact of T1AM on cardiomyocytes with a focus on the regulation of the intracellular temperature and natriuretic peptide (NP) expression. A thermoprobe was successfully introduced into neonatal rat cardiomyocytes, and the temperature-dependent changes in the fluorescence intensity ratio were measured using a fluorescence microscope. After one-hour incubation with T1AM, the degree of change in the fluorescence intensity ratio was significantly lower in T1AM-treated cardiomyocytes than in equivalent solvent-treated controls (P < 0.01), indicating the direct hypothermic action of T1AM on cardiomyocytes. Furthermore, T1AM treatment upregulated B-type NP (BNP) gene expression comparable to treatment with endothelin-1 or phenylephrine. Of note, ERK phosphorylation was markedly increased after T1AM treatment, and inhibition of ERK phosphorylation by an MEK inhibitor completely cancelled both T1AM-induced decrease in thermoprobe-measured temperature and the increase in BNP expression. In summary, T1AM decreases fluorescent thermoprobe-measured temperatures (estimated intracellular temperatures) and increases BNP expression in cardiomyocytes by activating the MEK/ERK pathway. The present findings provide new insight into the direct myocardial cellular actions of T1AM in patients with severe heart failure.

Pharmacognostical, phytochemical, antimicrobial and hepatoprotective screening of some plants of family rhamnaceae

Medicinal plants are used in traditional system of medicine to treat various diseases and many of these plants have been evaluated for their different pharmacological activities. Ziziphus mauritiana(ZM) (Rhamnaceae) is found wild and cultivated in many parts of India, Burma and Srilanka. Seeds of Ziziphus mauritianahave been reported to have sedative-hypnotic, hypotensive, antihypoxic, antihyperlipidemic and hypothermic activities. It is reported to contain minerals, alkaloids, flavonoids, sterols, tannins and saponins. Traditional medicine using herbal drugs exists in every part of the world. The major areas are Chinese, Indian and European traditions. The philosophies of these traditional medicines have some resemblance to each other but differ widely from modern western medicine. In view of the progress of western medicine not only new synthetic drugs but also herbal drugs have to fulfill the international requirements on quality, safety and efficacy. Herbal drugs have the advantage of being available for patients in the geographical area of the special traditional medicine. The development procedure of herbal drugs for world-wide use has to be different from that of synthetic drugs.

Dopaminergic input from the posterior hypothalamus to the raphe pallidus area inhibits brown adipose tissue thermogenesis.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

Dexmedetomidine in modern anesthesiology and intensive care

Background. Sedation is a controlled medical depression of consciousness with the preservation of protective reflexes, independent effective breathing and response to physical stimulation and verbal commands. Sedation is indicated for patients in the intensive care unit in presence of agitation, delirium, withdrawal syndrome of alcohol, drugs or other potent medications and the need to protect the brain (blunt traumatic brain injury, posthypoxic encephalopathy). In addition, at the request of the patient, sedation can be used during invasive diagnostic and treatment procedures.&#x0D; Objective. To describe the role of dexmedetomidine in modern anesthesiology and intensive care.&#x0D; Materials and methods. Analysis of literature data on this issue.&#x0D; Results and discussion. When performing sedation, one should balance between the excessive sedation and its absence. Excessive sedation is accompanied by the lack of contact with the patient, inability to assess the neurological status of the patient, and respiratory depression. If the patient is optimally sedated, he is calm and able to cooperate; he is also adapted to mechanical lung ventilation and other procedures. The target level of sedation according to the Richmond excitation-sedation scale is from 0 to -1. Drugs such as benzodiazepines (diazepam, midazolam, lorazepam), barbiturates (sodium thiopental), propofol, ketamine, inhaled anesthetics (sevoflurane, dexflurane), dexmedetomidine, opioids (morphine, fentanyl, remifentanyl) are used for sedation. Dexmedetomidine is a highly selective α2-adrenoagonist, so it has anxiolytic, sedative, antinociceptive, sympatholytic, and hypothermic actions. In addition, this drug reduces heart rate, suppresses tremor and increases diuresis. The sedative effect of dexmedetomidine is due to the inhibition of neuronal activity in the locus coeruleus of the brain stem. The condition caused by dexmedetomidine is similar to the natural sleep. The use of dexmedetomidine allows to achieve the target level of sedation in a higher percentage of cases than the use of other drugs (propofol, midazolam) (Jacub S.M. et al., 2012). Cooperative sedation is a sedation with the possibility of interaction of the patient with the medical staff. Compared to other drugs, dexmedetomidine increases the patient’s ability to wake up and quickly orient, after which the patient can quickly return to a state of sedation. One of the major complications of critically serious diseases and their treatment is the deterioration of cognitive abilities. Dexmedetomidine has been shown to improve the patient’s cognitive performance by 6.8 points on the John Hopkins scale. In contrast, propofol reduces cognitive function by an average of 12.4 points (Mirski M.A. et al., 2010). Dexmedetomidine has no respiratory depressant effect. Patients on mechanical ventilation do not require discontinuation of dexmedetomidine prior to extubation. Importantly, dexmedetomidine increases coronary blood flow, reduces the incidence of perioperative myocardial ischemia and the risk of perioperative cardiac death. Dexmedetomidine reduces the intensity of pain in the postoperative period and the need for opioids, the incidence of delirium, and the duration of mechanical ventilation. The financial and economic reasonability of dexmedetomidine use has been proved.&#x0D; Conclusions. 1. Sedation is indicated for patients in the intensive care unit in presence of agitation, delirium, withdrawal syndrome and the need to protect the brain, as well as during invasive diagnostic and treatment procedures. 2. The target level of sedation is from 0 to -1 on the Richmond excitation-sedation scale. 3. Dexmedetomidine is a highly selective α2-adrenoagonist, which has anxiolytic, sedative, antinociceptive, sympatholytic, and hypothermic action. 4. Dexmedetomidine increases coronary blood flow and reduces the incidence of perioperative myocardial ischemia, the risk of perioperative cardiac death, pain, delirium incidence and the duration of mechanical ventilation.

Hypothermia Advocates Functional Mitochondria and Alleviates Oxidative Stress to Combat Acetaminophen-Induced Hepatotoxicity.

For years, moderate hypothermia (32 °C) has been proposed as an unorthodox therapy for liver injuries, with proven hepatoprotective potential. Yet, limited mechanistic understanding has largely denied its acceptance over conventional pharmaceuticals for hepatoprotection. Today, facing a high prevalence of acetaminophen-induced liver injury (AILI) which accounts for the highest incidence of acute liver failure, hypothermia was evaluated as a potential therapy to combat AILI. For which, transforming growth factor-α transgenic mouse hepatocytes (TAMH) were subjected to concomitant 5 mM acetaminophen toxicity and moderate hypothermic conditioning for 24 h. Thereafter, its impact on mitophagy, mitochondrial biogenesis, glutathione homeostasis and c-Jun N-terminal kinase (JNK) signaling pathways were investigated. In the presence of AILI, hypothermia displayed simultaneous mitophagy and mitochondrial biogenesis to conserve functional mitochondria. Furthermore, antioxidant response was apparent with higher glutathione recycling and repressed JNK activation. These effects were, however, unremarkable with hypothermia alone without liver injury. This may suggest an adaptive response of hypothermia only to the injured sites, rendering it favorable as a potential targeted therapy. In fact, its cytoprotective effects were displayed in other DILI of similar pathology as acetaminophen i.e., valproate- and diclofenac-induced liver injury and this further corroborates the mechanistic findings of hypothermic actions on AILI.

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia.

Therapeutic hypothermia represents a brain-protective strategy for multiple emergency situations, such as stroke or traumatic injury. Neurotensin (NT), which exerts its effects through activation of two G protein-coupled receptors, namely NTS1 and NTS2, induces a strong and long-lasting decrease in core body temperature after its central administration. Growing evidence demonstrates that NTS1 is the receptor subtype mediating the hypothermic action of NT. As such, potent NTS1 agonists designed on the basis of the minimal C-terminal NT(8-13) bioactive fragment have been shown to produce mild hypothermia and exert neuroprotective effects under various clinically relevant conditions. The high susceptibility of NT(8-13) to protease degradation (half-life <2 min) represents, however, a serious limitation for its use in pharmacological therapy. In light of this, we report here a structure-activity relationship study in which pairs of NT(8-13) analogs have been developed, based on the incorporation of a reduced Lys8-Lys9 bond. To further stabilize the peptide bonds, a panel of backbone modifications was also inserted along the peptide sequence, including Sip10, D-Trp11, Dmt11, Tle12, and TMSAla13. Our results revealed that the combination of appropriate chemical modifications leads to compounds exhibiting improved resistance to proteolytic cleavages (>24 h; 16). Among them, the NT(8-13) analogs harboring the reduced amine bond combined with the unnatural amino acids TMSAla13 (4) and Sip10 (6) or the di-substitution Lys11 - TMSAla13 (12), D-Trp11-TMSAla13 (14), and Dmt11-Tle12 (16) produced sustained hypothermic effects (−3°C for at least 1 h). Importantly, we observed that hypothermia was mainly driven by the increased stability of the NT(8-13) derivatives, instead of the high binding-affinity at NTS1. Altogether, these results reveal the importance of the reduced amine bond in optimizing the metabolic properties of the NT(8-13) peptide and support the development of stable NTS1 agonists as first drug candidate in neuroprotective hypothermia.

Trace Amine-Associated Receptor 5 Provides Olfactory Input Into Limbic Brain Areas and Modulates Emotional Behaviors and Serotonin Transmission.

Trace amine-associated receptors (TAARs) are a class of G-protein-coupled receptors found in mammals. While TAAR1 is expressed in several brain regions, all the other TAARs have been described mainly in the olfactory epithelium and the glomerular layer of the olfactory bulb and are believed to serve as a new class of olfactory receptors sensing innate odors. However, there is evidence that TAAR5 could play a role also in the central nervous system. In this study, we characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO) expressing beta-galactosidase mapping TAAR5 expression. We found that TAAR5 is expressed not only in the glomerular layer in the olfactory bulb but also in deeper layers projecting to the limbic brain olfactory circuitry with prominent expression in numerous limbic brain regions, such as the anterior olfactory nucleus, the olfactory tubercle, the orbitofrontal cortex (OFC), the amygdala, the hippocampus, the piriform cortex, the entorhinal cortex, the nucleus accumbens, and the thalamic and hypothalamic nuclei. TAAR5-KO mice did not show gross developmental abnormalities but demonstrated less anxiety- and depressive-like behavior in several behavioral tests. TAAR5-KO mice also showed significant decreases in the tissue levels of serotonin and its metabolite in several brain areas and were more sensitive to the hypothermic action of serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propilamino)tetralin (8-OH-DPAT). These observations indicate that TAAR5 is not just innate odor-sensing olfactory receptor but also serves to provide olfactory input into limbic brain areas to regulate emotional behaviors likely via modulation of the serotonin system. Thus, anxiolytic and/or antidepressant action of future TAAR5 antagonists could be predicted. In general, “olfactory” TAAR-mediated brain circuitry may represent a previously unappreciated neurotransmitter system involved in the transmission of innate odors into emotional behavioral responses.

Inhibition of lipolysis: A novel explanation for the hypothermic actions of acetaminophen in non-febrile rodents

Acetaminophen is both widely used to treat children with fever and is also responsible for thousands being hospitalised annually. Historically the antipyretic actions of acetaminophen were attributed to the inhibition of cyclooxygenase (COX-1/2) enzymes and more recently a novel COX-1 variant (COX-3) located in the brain. However, the evidence for acetaminophen-mediated COX inhibition remains contentious. This study assesses the impact of acetaminophen and other putative COX-3 inhibitors on the release of fatty acids during lipolysis as an alternative mechanism by which antipyretics can reduce body temperature during fever. 3T3-L1 adipocytes, primary brown adipocytes and isolated mitochondria were exposed to COX-3 inhibitors and lipolysis and mitochondrial electron transport chain function assessed. Acetaminophen, aminopyrine and antipyrine at 1–10 mM caused a significant decrease (up to 70%; P < 0.01, from control) in lipolysis within 1, 3 and 24 h without affecting cell viability. The inhibition was observed regardless of where along its signalling pathway lipolysis was stimulated. All three compounds were found to significantly attenuate mitochondrial function by up to 30% for complex I and 40% for complex II (P < 0.01, from control). These novel observations combined with the known limited inhibition of the COX enzymes by acetaminophen suggest both the antipyretic and hypothermia induced by acetaminophen and related compounds could be attributed to the direct inhibition of lipolysis and mitochondrial function, rather than cyclooxygenase inhibition centrally. Further these observations could provide new drug targets for reducing fever with the added bonus of fewer individuals being hospitalized by accidental acetaminophen overdose.

Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E2 (PGE2) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE2-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE2 biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.

Heat Stress Biomarker Amino Acids and Neuropeptide Afford Thermotolerance in Chicks.

With global warming, heat stress is becoming a pressing concern worldwide. In chickens, heat stress reduces food intake and growth, and increases body temperature and stress responses. Although it is believed that young chicks do not experience heat stress as they need a higher ambient temperature to survive, our series of studies in young chicks showed that they are sensitive to heat stress. This review summarizes current knowledge on amino acid metabolisms during heat stress, with special emphasis on the hypothermic functions of l-citrulline (l-Cit) and l-leucine (l-Leu), and the functions of neuropeptide Y (NPY) in terms of body temperature and heat stress regulation in chicks. Amino acid metabolism is severely affected by heat stress. For example, prolonged heat stress reduces plasma l-Cit in chicks and l-Leu in the brain and liver of embryos. l-Cit and l-Leu supplementation affords thermotolerance in young chicks. NPY expression is increased in the brains of heat-exposed chicks. NPY has a hypothermic action under control thermoneutral temperature and heat stress in chicks. The NPY-sub-receptor Y5 is a partial mediator of the hypothermic action of NPY. Further, NPY stimulates brain dopamine concentrations and acts as an anti-stress agent in heat-exposed fasted, but not fed chicks. In conclusion, young chicks can serve as a model animal for the study of heat stress in chickens. l-Cit, l-Leu, and NPY were identified as biomarkers of heat stress, with the potential to afford thermotolerance in chicks.

Evaluation of hypothermic activity of preparations with local anaesthesia activity according to contactless IR-thermometry data

Цель - оценить гипотермическую активность местноанестезирующих препаратов, как средств выбора профилактики постинъекционных осложнений у пациентов с хроническим рецидивирующим герпесом. Материалы и методы. Использованы препараты на основе 10% лидокаина, 20% бензокаина и хелатного германийорганического соединения. Инфракрасным термометром измеряли температуру слизистой оболочки рта до нанесения, во время, через 1, 2 и 5 минут после аппликации геля, а также проводили измерение артериального давления. Результаты. При сравнении германийсодержащего хелатного соединения и геля на основе 20% бензокаина данные уровня значимости показали отсутствие статистической разницы (p=0,2), что указывает на возможность выбора обоих препаратов для клинической практики. При пониженной изначальной температуре у гипотоников, у нормо- и гипертоников отмечается неполное восстановление температуры через 5 минут после нанесения геля. Гель на основе хелатного комплекса германийорганического соединения с гуанином оказывает наибольший гипотермический эффект. Локальная гипотермия показала высокую эффективность без осложнений в виде рецидива хронического рецидивирующего герпеса. Выводы. Гель на основе германийорганического хелатного соединения в виде аппликаций может быть использован для профилактики рецидива хронического рецидивирующего герпеса. Гипотермические свойства геля германийорганического хелатного соединения рекомендовано использовать как совместно с аппликационным анестетиком, так и изолированно от него, что расширяет показания к его применению.

Influence of extracts from Rhodiola rosea and Rhodiola kirilowii on the development of alcohol tolerance in rats

Summary Introduction: Rhodiola rosea (RR) and Rhodiola kirilowii (RK) are well known for their influence on central nervous system, however their impact on the development of alcohol tolerance has not yet been proven. Objective: The aim of this study was to determine the ability of RR and RK roots extracts to inhibit the development of alcohol tolerance in vivo, both, peripheral (metabolic) and central ones. Methods: Male Wistar rats were treated with RR and RK extracts (p.o.) and ethanol (i.p.) for ten consecutive days. On the first, third, fifth and eighth days the hypothermic action of ethanol was measured, while on the ninth day the loss of righting reflex was examined. On the tenth day rats were treated with assigned extract and sacrificed 1 h after the ethanol injection. Results: Both extracts inhibited development of tolerance to the hypothermic action of ethanol. The observed effect seems to be specific since none of the extracts affected body temperature in water-treated animals. RK extract also prolonged the hypnotic action of ethanol. RR-treated rats had higher blood-ethanol concentrations, in contrast to RK ones. Conclusions: RR and RK extracts inhibited the development of tolerance to the hypothermic action of ethanol. Prolongation of the hypnotic action of ethanol by RK extract may be associated with influence on the central nervous system, while the RR one also inhibited the development of metabolic tolerance.

Influence of salidroside, a neuroactive compound of Rhodiola rosea L., on alcohol tolerance development in rats

Summary Introduction: In recent years, the search for potential neuroprotective properties of salidroside and its ability to influence the activity of nervous system become the subject of intense studies of many research groups. None of these studies, however, include an attempt to determine the effect of salidroside on the course of alcohol tolerance in vivo. Objective: The aim of this study was to investigate the ability of salidroside to inhibit the development of alcohol tolerance in rats, determining whether the effect of its action may occur in a dose-dependent manner, reducing both metabolic and central tolerance without affecting body temperature in control rats. Methods: Male Wistar rats were injected daily with ethanol at a dose of 3 g/kg for 9 consecutive days to produce ethanol tolerance. Salidroside in two doses (4.5 mg/kg and 45 mg/kg b.w.) or vehiculum was administered orally. On the 1st, 3rd, 5th and 8th day a hypothermic effect of ethanol was measured, while the loss of righting reflex procedure was performed on the 2nd, 4th, 6th and 7th day. On the 9th day rats were treated with salidroside, sacrificed 1 h after ethanol injections and blood was collected for blood-ethanol concentration measurement. Results: Salidroside at a dose of 45 mg/kg inhibited the development of tolerance to hypothermic and sedative effects of ethanol, whereas insignificant elevation of blood-ethanol concentration was observed. The dose of 4.5 mg/kg b.w. had minimal effect, only small inhibition of tolerance to hypothermic action was observed. Salidroside affected neither body mass growth nor body temperature in non-alcoholic (control) rats. Conclusions: Results of the study indicate that salidroside at a dose of 45 mg/kg inhibited the development of tolerance to the hypothermic effect of ethanol. Observed inhibition of tolerance to the sedative effect of ethanol seems to be associated with salidroside influence on the central nervous system. A comprehensive explanation of the abovementioned observations requires further pharmacological and pharmacodynamic studies.

Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP)=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.

Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen.

Acetaminophen (AcAP), a widely-used antipyretic and analgesic drug, has been considered to exert its effects via central mechanisms, and many studies have demonstrated that the analgesic action of AcAP involves activation of the serotonergic system. Although the serotonergic system also plays an important role in thermoregulation, the contribution of serotonergic activity to the hypothermic effect of AcAP has remained unclear. In the present study, we examined whether the serotonergic system is involved in AcAP-induced hypothermia. In normal mice, AcAP (300 mg/kg, intraperitoneally (i.p.)) induced marked hypothermia (ca. -4°C). The same dose of AcAP reduced pain response behavior in the formalin test. Pretreatment with the serotonin synthesis inhibitor DL-p-chlorophenylalanine (PCPA, 300 mg/kg/d, i.p., 5 consecutive days) substantially decreased serotonin in the brain by 70% and significantly inhibited the analgesic, but not the hypothermic action of AcAP. The same PCPA treatment significantly inhibited the hypothermia induced by the selective serotonin reuptake inhibitor fluoxetine hydrochloride (20 mg/kg, i.p.) and the serotonin 5-HT2 receptor antagonist cyproheptadine hydrochloride (3 mg/kg, i.p.). The lower doses of fluoxetine hydrochloride (3 mg/kg, i.p.) and cyproheptadine hydrochloride (0.3 mg/kg, i.p.) did not affect the AcAP-induced hypothermia. These results suggest that, in comparison with its analgesic effect, the hypothermic effect of AcAP is not mediated by the serotonergic system.

Hypothermic activity of acetaminophen; involvement of GABAA receptor, theoretical and experimental studies.

The mechanism of hypothermia action of acetaminophen (APAP) remains unclear even 125 years after its synthesis. Acetaminophen produces hypothermia. The mechanism of this reduction in core body temperature is not clear but evidence shows that it is not dependent on opioid and cannabinoid receptors. Because of strong documents about the roles of GABA and benzodiazepine receptors in hypothemic activity of some drugs such as diazepam, we determined if these receptors also contributes to the hypothermic effect of APAP. Diazepam (5 mg/kg, IP) was used for induction of hypothermia. Flumazenil (10 mg/kg, IP) or picrotoxin (2 mg/kg, IP) used for reversal of this effect. Rats injected with APAP (100, 200 or 300 mg/kg, IP). Baseline temperature measurements were taken with a digital thermometer via rectum. To evaluate the structural correlation between APAP and benzodiazepine receptor ligands, numerous models are selected and studied at HF/6-31G* level of theory. Relative energies, enthalpies and Gibbs free energies were calculated for all selected drugs. Diazepam induced hypothermia was reversed by flumazenil or picrotoxin. Rats injected with APAP displayed dose- and time-related hypothermia. For combined administration, the hypothermic effect of APAP (200 mg/kg) was strongly reduced by pretreatment with picrotoxin or flumazenil P<0.0001and P<0.01, respectively. Selective structural data, bond length, dihedral angles, and related distance in pharmacophore of APAP and BZDR models were the same. Some significant structural analogues were obtained between these drugs. Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor.

The Role of Transmural Repolarization Gradient in the Inversion of Cardiac Electric Field: Model Study of ECG in Hypothermia.

The changes in ventricular repolarization gradients lead to significant alterations of the electrocardiographic body surface T waves up to the T wave inversion. However, the contribution of a specific gradient remains to be elucidated. The objective of the present investigation was to study the role of the transmural repolarization gradient in the inversion of the body surface T wave with a mathematical model of the hypothermia-induced changes of ventricular repolarization. By means of mathematical simulation, we set the hypothermic action potential duration (APD) distribution on the rabbit ventricular epicardium as it was previously experimentally documented. Then the parameters of the body surface potential distribution were tested with the introduction of different scenarios of the endocardial and epicardial APD behavior in hypothermia resulting in the unchanged, reversed or enlarged transmural repolarization gradient. The reversal of epicardial repolarization gradients (apicobasal, anterior-posterior and interventricular) caused the inversion of the T waves regardless of the direction of the transmural repolarization gradient. However, the most realistic body surface potentials were obtained when the endocardial APDs were not changed under hypothermia while the epicardial APDs prolonged. This produced the reversed and increased transmural repolarization gradient in absolute magnitude. The body surface potentials simulated under the unchanged transmural gradient were reduced in comparison to those simulated under the reversed transmural gradient. The simulations demonstrated that the transmural repolarization gradient did not play a crucial role in the cardiac electric field inversion under hypothermia, but its magnitude and direction contribute to the T wave amplitude.

Evidence for effects on thermoregulation after acute oral exposure to type I and type II pyrethroids in infant rats

Most pyrethroid (PYR) insecticides may be classified either as type-I compounds, which produce whole body tremors and hyperthermia, or type-II compounds, which produce salivation, choreoathetosis, and hypothermia (i.e., producing T and CS neurobehavioral syndromes, respectively). This classification is based on clinical observations in adult rats and mice after intracerebroventricular or intravascular administration of highly effective acute (bolus) doses. PYR neurotoxicity in infant animals is not characterized as much as in adult animals. Endpoints informing on vital determinants of mammal's maturation, such as body temperature may help recognizing age-related differences in susceptibility to PYRs. In this work, body temperature (Tb) was monitored at 30-min intervals after acute oral exposure to T-syndrome PYR bifenthrin (BIF), CS-syndrome PYR cypermethrin (CYPM), and a BIF–CYPM mixture in weanling rats by using a subcutaneous temperature monitoring system. In both single-compound assays, a time- and dose-related decline of Tb was the most evident impact on thermoregulation observed starting at ~2–3h after dosing. Moreover, 15–18mg/kg BIF induced a mild increase in Tb before the hypothermic action was apparent. The lowest effective dose for temperature perturbation was 15mg/kg for BIF and 10mg/kg for CYPM, and moderate neurobehavioral alterations were evident at 12 and 10mg/kg, respectively. When low effective doses of BIF and CYPM were co-administered mild behavioral effects and a transient increase in Tb (p=0.02) were observed at 1–2h, and no Tb decline was apparent afterwards compared to control animals. Noteworthy, the hypothermic action of BIF in infant rats was quite different from the hyperthermia consistently reported in studies using mature animals. Our results suggest that body temperature monitoring may be useful as a complementary assessment to reveal qualitative age-specific pesticide effects in rats.