The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice.

Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1-/-) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5-1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1-/- mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.

POLAR Study Revisited: Therapeutic Hypothermia in Severe Brain Trauma Should Not Be Abandoned.

The benefits of therapeutic hypothermia (TH) in severe traumatic brain injury (sTBI) have been long debated. In 2018, the POLAR study, a high-quality international trial, appeared to end the debate by showing that TH did not improve mortality in sTBI. However, the POLAR-based recommendation to abandon TH was challenged by different investigators. In our recent meta-analysis, we introduced the cooling index (COIN) to assess the extent of cooling and showed that TH is beneficial in sTBI, but only when the COIN is sufficiently high. In the present study, we calculated the COIN for the POLAR study and ran a new meta-analysis, which included the POLAR data and accounted for the cooling extent. The POLAR study targeted a high cooling extent (COIN of 276°C × h; calculated for 72 h), but the achieved cooling was much lower (COIN of 193°C × h)-because of deviations from the protocol. When the POLAR data were included in the COIN-based meta-analysis, TH had an overall effect of reducing death (odds rate of 0.686; p = 0.007). Among the subgroups with different COIN levels, the only significantly decreased odds rate (i.e., beneficial effect of TH) was observed in the subgroup with high COIN (0.470; p = 0.013). We conclude that, because of deviations from the targeted cooling protocol, the overall cooling extent was not sufficiently high in the POLAR study, thus masking the beneficial effects of TH. The current analysis shows that TH is beneficial in sTBI, but only when the COIN is high. Abandoning the use of TH in sTBI may be premature.

Uninterrupted or Minimally Interrupted Direct Oral Anticoagulant Therapy is a Safe Alternative to Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation: An Updated Meta-Analysis.

Adequate anticoagulation during catheter ablation (CA) for atrial fibrillation (AF) is crucial for the prevention of both thromboembolic events and life-threatening bleeding. The purpose of this updated meta-analysis is to compare the safety and efficacy of uninterrupted and minimally interrupted periprocedural direct oral anticoagulant (DOAC) protocols and uninterrupted vitamin K antagonist (VKA) therapy in patients undergoing CA for AF based on the latest evidence. Randomized controlled trials, prospective observational studies, and retrospective registries comparing DOACs to VKAs were identified in multiple databases (Embase, MEDLINE via PubMed, CENTRAL, and Scopus). The primary outcomes were stroke or transient ischemic attack (TIA), major bleeding, and net clinical benefit. Forty-two studies with a total of 22,715 patients were included in the final analysis. The occurrence of major bleeding was significantly lower in patients assigned to uninterrupted DOAC treatment compared to VKAs (pooled odds ratio (POR): 0.71, confidence interval (CI): 0.51-0.99). The pooled analysis of both uninterrupted and minimally interrupted DOAC groups also showed significant reduction in major bleeding events (POR: 0.70, CI: 0.53-0.93). The incidence of thromboembolic events was low, with no significant difference between groups. This updated meta-analysis showed that DOAC therapy is as effective as VKA in preventing stroke and TIA. Minimally interrupted DOAC therapy is a non-inferior periprocedural anticoagulation strategy; however, uninterrupted DOAC therapy showed superiority compared to VKA with regard to major, life-threatening bleeding. Based on our in-depth analysis, we conclude that both DOAC strategies are equally safe and preferable alternatives to VKAs in patients undergoing CA for AF.

Bidirectional Relationship Between Reduced Blood pH and Acute Pancreatitis: A Translational Study of Their Noxious Combination.

Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP.

Therapeutic Whole-Body Hypothermia Reduces Death in Severe Traumatic Brain Injury if the Cooling Index Is Sufficiently High: Meta-Analyses of the Effect of Single Cooling Parameters and Their Integrated Measure.

Therapeutic hypothermia was investigated repeatedly as a tool to improve the outcome of severe traumatic brain injury (TBI), but previous clinical trials and meta-analyses found contradictory results. We aimed to determine the effectiveness of therapeutic whole-body hypothermia on the deaths of adult patients with severe TBI by using a novel approach of meta-analysis. We searched the PubMed, EMBASE, and Cochrane Library databases from inception to February 2017. The identified human studies were evaluated regarding statistical, clinical, and methodological designs to ensure interstudy homogeneity. We extracted data on TBI severity, body temperature, death, and cooling parameters; then we calculated the cooling index, an integrated measure of therapeutic hypothermia. Forest plot of all identified studies showed no difference in the outcome of TBI between cooled and not cooled patients, but interstudy heterogeneity was high. On the contrary, by meta-analysis of randomized clinical trials that were homogenous with regard to statistical, clinical designs, and precisely reported the cooling protocol, we showed decreased odds ratio for death in therapeutic hypothermia compared with no cooling. As independent factors, milder and longer cooling, and rewarming at <0.25°C/h were associated with better outcome. Therapeutic hypothermia was beneficial only if the cooling index (measure of combination of cooling parameters) was sufficiently high. We conclude that high methodological and statistical interstudy heterogeneity could underlie the contradictory results obtained in previous studies. By analyzing methodologically homogenous studies, we show that cooling improves the outcome of severe TBI, and this beneficial effect depends on certain cooling parameters and on their integrated measure, the cooling index.

The Neurokinin-1 Receptor Contributes to the Early Phase of Lipopolysaccharide-Induced Fever via Stimulation of Peripheral Cyclooxygenase-2 Protein Expression in Mice.

Neurokinin (NK) signaling is involved in various inflammatory processes. A common manifestation of systemic inflammation is fever, which is usually induced in animal models with the administration of bacterial lipopolysaccharide (LPS). A role for the NK1 receptor was shown in LPS-induced fever, but the underlying mechanisms of how the NK1 receptor contributes to febrile response, especially in the early phase, have remained unknown. We administered LPS (120 µg/kg, intraperitoneally) to mice with the Tacr1 gene, i.e., the gene encoding the NK1 receptor, either present (Tacr1+/+ ) or absent (Tacr1-/- ) and measured their thermoregulatory responses, serum cytokine levels, tissue cyclooxygenase-2 (COX-2) expression, and prostaglandin (PG) E2 concentration. We found that the LPS-induced febrile response was attenuated in Tacr1-/- compared to their Tacr1+/+ littermates starting from 40 min postinfusion. The febrigenic effect of intracerebroventricularly administered PGE2 was not suppressed in the Tacr1-/- mice. Serum concentration of pyrogenic cytokines did not differ between Tacr1-/- and Tacr1+/+ at 40 min post-LPS infusion. Administration of LPS resulted in amplification of COX-2 mRNA expression in the lungs, liver, and brain of the mice, which was statistically indistinguishable between the genotypes. In contrast, the LPS-induced augmentation of COX-2 protein expression was attenuated in the lungs and tended to be suppressed in the liver of Tacr1-/- mice compared with Tacr1+/+ mice. The Tacr1+/+ mice responded to LPS with a significant surge of PGE2 production in the lungs, whereas Tacr1-/- mice did not. In conclusion, the NK1 receptor is necessary for normal fever genesis. Our results suggest that the NK1 receptor contributes to the early phase of LPS-induced fever by enhancing COX-2 protein expression in the periphery. These findings advance the understanding of the crosstalk between NK signaling and the "cytokine-COX-2-prostaglandin E2" axis in systemic inflammation, thereby open up the possibilities for new therapeutic approaches.