Thermoregulatory Dysfunction Research Articles

Excessive yawning and thermoregulatory dysfunction

Excessive yawning and thermoregulatory dysfunction

Discovery of Novel Selective Norepinephrine Reuptake Inhibitors: 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231)

Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.

Thermoregulatory, behavioral, and metabolic responses to heatstroke in a conscious mouse model

The typical core temperature (T(c)) profile displayed during heatstroke (HS) recovery consists of initial hypothermia followed by delayed hyperthermia. Anecdotal observations led to the conclusion that these T(c) responses represent thermoregulatory dysfunction as a result of brain damage. We hypothesized that these T(c) responses are mediated by a change in the temperature setpoint. T(c) (+/- 0.1 degrees C; radiotelemetry) of male C57BL/6J mice was monitored while they were housed in a temperature gradient with ambient temperature (T(a)) range of 20-39 degrees C to monitor behaviorally selected T(a) (T(s)) or an indirect calorimeter (T(a) = 25 degrees C) to monitor metabolism (V(O(2))) and calculate respiratory exchange ratio (RER). Responses to mild and severe HS (thermal area 249.6 +/- 18.9 vs. 299.4 +/- 19.3 degrees C.min, respectively) were examined through 48 h of recovery. An initial hypothermia following mild HS was associated with warm T(s) (approximately 32 degrees C), approximately 35% V(O(2)) decrease, and RER approximately 0.71 that indicated reliance on fatty acid oxidation. After 24 h, mild HS mice developed hyperthermia associated with warm T(s) (approximately 32 degrees C), approximately 20% V(O(2)) increase, and RER approximately 0.85. Severe HS mice appeared poikilothermic-like in the temperature gradient with T(c) similar to T(s) (approximately 20 degrees C), and these mice failed to recover from hypothermia and develop delayed hyperthermia. Cellular damage (hematoxylin and eosin staining) was undetectable in the hypothalamus or other brain regions in severe HS mice. Overall, decreases and increases in T(c) were associated with behavioral and autonomic thermoeffectors that suggest HS elicits anapyrexia and fever, respectively. Taken together, T(c) responses of mild and severe HS mice suggest a need for reinterpretation of the mechanisms of thermoregulatory control during recovery.

Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter.

The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.

Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors

A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified ( +)- S- 21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.

Yawning, sleep, and symptom relief in patients with multiple sclerosis

Background Patients with multiple sclerosis (MS) suffer from thermoregulatory dysfunction, and repetitive yawning and sleep problems are symptoms of MS. Because yawning and sleep are involved in thermoregulation, we investigated the association between yawning, sleep, and symptom relief in patients with MS. Methods Sixty patients filled out a questionnaire about how often they yawned, whether yawning provided relief of MS symptoms, and how sleep affected these symptoms. Results Results showed that over one in three patients reported that their MS symptoms improved following a yawn, and of those experiencing relief, nearly half reported that it lasted for several minutes or longer. Not getting a good night’s sleep often made MS symptoms worse, while napping during the day provided symptom relief. Conclusion This is the first study showing that yawning provides symptom relief in patients with multiple sclerosis.

1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as Potent and Selective Norepinephrine Reuptake Inhibitors

Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.

Structure–activity relationships of norepinephrine reuptake inhibitors with benzothiadiazine dioxide or dihydrosulfostyril cores

Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1 H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure–activity relationships were determined for the series’ in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.

Protective effect of transgenic expression of porcine heat shock protein 70 on hypothalamic ischemic and oxidative damage in a mouse model of heatstroke

BackgroundTransgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70β gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke.ResultsWe report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4°C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2°C ± 0.4°C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4°C ± 0.3°C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression.ConclusionThis study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.

1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: Potent, Selective, and Orally Efficacious Norepinephrine Reuptake Inhibitors

Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.

Excessive yawning and thermoregulation: two case histories of chronic, debilitating bouts of yawning

This report details the case histories of two women who suffer from chronic and debilitating episodes of excessive yawning in the absence of sleep problems. Each woman independently provided information and answered questions about their excessive yawning symptoms and medical histories. Both women show signs of thermoregulatory dysfunction, and each reports symptom relief and/or the postponement of yawning attacks through means of behavioral cooling. One woman recorded her body temperature before and after bouts of yawning, revealing a significant drop in temperature following each episode (p < 0.05). The trigger for yawning in these patients appears to be related to increases in body/brain temperature. These cases are consistent with growing evidence showing that recurrent episodes of excessive yawning are not necessarily associated with a sleep disorder, but rather may be indicative of thermoregulatory dysfunction.

Medical implications of excessive yawning in relation to thermoregulatory dysfunction

Medical implications of excessive yawning in relation to thermoregulatory dysfunction

What causes hot flushes? The neuroendocrine origin of vasomotor symptoms in the menopause

Vasomotor symptoms (VMS) such as hot flushes and night sweats are frequently encountered during menopause and can greatly reduce the quality of life. These symptoms are causally related to decreasing estradiol concentrations, mainly in the serum and subsequently also in the hypothalamic temperature regulating centre. The lack of estrogens alters neurotransmitter activity, especially in the serotonergic and noradrenergic pathways. Because sex steroids act as potent neuromodulators, the substitution of ovarian sex steroids by hormone replacement therapy is the most effective treatment option for VMS. When contraindications exist for the use of sex steroids, steroid-free drugs are a possible alternative. A better understanding of the physiology of thermoregulation, thermoregulatory dysfunction and adaptive processes of the brain may facilitate the development of new therapeutic approaches. Such drugs could then be used to treat vasomotor disorders even when the use of steroid hormones is contraindicated. This review article summarises our knowledge on the mechanisms of temperature regulation and describes deviations from this regulation during altered sex steroid conditions. Our current knowledge on neuroendocrinology of thermoregulation may serve as a basis for the use of steroid-free pharmacological intervention.

Fatal Fever of Unknown Origin in Acute Cervical Spinal Cord Injury: Five Cases

Background/Objective: Patients with traumatic upper thoracic and cervical spinal cord injuries are at increased risk for the development of autonomic dysfunction, including thermodysregulation. Thermoregulation is identified as an autonomic function, although the exact mechanisms of thermodysregulation have not been completely recognized. Quad fever is a hyperthermic thermoregulatory disorder that occurs in people with acute cervical and upper thoracic spinal cord injuries. First described in 1982, it has not been widely discussed in the literature.Methods: Case reports of 5 patients with cervical spinal cord injury (SCI).Results: Five of 18 patients (28%) with acute cervical SCI who were admitted during a 1-year period had fatal complications caused by persistent hyperthermia of unknown origin.Conclusions: Patients with acute traumatic cervical and upper thoracic SCI are at risk for thermoregulatory dysfunction. Changes in the hypothalamic axis may be implicated, especially in the light of modification in hypothalamic afferent nerves, but this hypothesis has not yet been explored. Thermodysregulation may be an early sign of autonomic dysfunction. A comprehensive guideline is needed for the management of elevated body temperature in critically ill patients with cervical SCI, because this condition may be fatal.

Simultaneous telemetric monitoring of tail-skin and core body temperature in a rat model of thermoregulatory dysfunction

Temperature dysfunction, clinically described as hot flashes/flushes and night sweats, commonly occur in women transitioning through menopause. Research in this field has yet to fully elucidate the biological underpinnings explaining this dysfunction. The need to develop animal models that can be used to study hormone-dependent temperature regulation is essential to advancing this scientific area. Development of telemetric transmitters for monitoring tail-skin (TST) and core body (CBT) temperatures for animal research has increased the accuracy of data by reducing extraneous factors associated with previous methods. However, until recently, TST and CBT could not be simultaneously measured telemetrically within the same animal. In this report, new dual temperature monitoring transmitters were validated by simultaneously evaluating them with the single measurement transmitters using the ovariectomized (OVX) rat thermoregulatory dysfunction model. A major advantage of measuring TST and CBT in the same animal is the ability to relate temporal changes on these two temperature parameters. Comparative experimentation was performed by single administration of clonidine (alpha2 adrenergic agonist), MDL-100907 (5-HT2a antagonist), or a 7-day treatment of 17α-ethinyl estradiol (EE). Clonidine caused decreases in TST and CBT, MDL-100907 caused increases in TST while decreasing CBT, and EE caused decreases in TST with minor CBT decreases only at the higher dose. Data from either probe type showed similar results on temperature parameters regardless of transmitter used. These findings support the use of the new dual temperature transmitters and should enhance the quality and interpretation of data being generated in thermoregulation studies.

Structure−Activity Relationships of the Cycloalkanol Ethylamine Scaffold: Discovery of Selective Norepinephrine Reuptake Inhibitors

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.

Repeat exposure to ciguatoxin leads to enhanced and sustained thermoregulatory, pain threshold and motor activity responses in mice: Relationship to blood ciguatoxin concentrations

Ciguatera is a common illness in tropical and subtropical regions that manifests in complex and long-lived symptoms which are more severe in subsequent exposures. This study measures central and peripheral neurologic signs, in parallel with blood toxin levels, in mice exposed once or twice (at 3 days interval) to a sublethal dose of ciguatoxin P-CTX-1 (0.26 ng/g via i.p.). Mice were implanted with radiotransmitters to monitor motor activity and core temperature. A single exposure to ciguatoxin elicited an immediate and transient decrease in motor activity and temperature, and subsequent long-lasting thermoregulatory dysfunction resulting in stabilized body temperature around 36.0 °C with no observable circadian rhythm. The hypothermic response and the reduced activity were enhanced with a second exposure with 30% of the mice dying within 7 h. Measurement of the peripheral nervous system by the tail flick assay revealed increased latency with a single ciguatoxin exposure, and a greater effect following the second exposure. Toxin was measurable in blood up to 3 days following the first exposure; at the 1 h time point the concentrations were significantly elevated after a second exposure. These findings indicate an early response to ciguatoxin manifest in a central response to lower body temperature and reduce motor activity and a more persistent effect on the peripheral system leading to spinal heat antinociception and delayed fever-like response. The greater neurological response to a second ciguatoxin exposure was associated with elevated concentrations of ciguatoxin in the blood solely over the first hour of exposure. In conclusion, a single exposure to toxin exerts a significant neurological response which may be enhanced with subsequent exposure.

Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages

Vasomotor symptoms (VMS), commonly called hot flashes or flushes (HFs) and night sweats, are the menopausal symptoms for which women seek treatment during menopause most often. VMS are a form of temperature dysfunction that occurs due to changes in gonadal hormones. Normally, core body temperature (CBT) remains within a specific range, oscillating with daily circadian rhythms. Physiological processes that conserve and dissipate heat are responsible for maintaining CBT, and tight regulation is important for maintenance of optimal internal organ function. Disruption of this tightly controlled temperature circuit results in exaggerated heat-loss responses and presents as VMS. The mechanistic role related to changes in gonadal hormones associated with VMS is not understood. Hormone therapy is the most effective treatment for VMS and other menopausal symptoms. Estrogens are known potent neuromodulators of numerous neuronal circuits throughout the central nervous system. Changing estrogen levels during menopause may impact multiple components involved in maintaining temperature homeostasis. Understanding the pathways and mechanisms involved in temperature regulation, probable causes of thermoregulatory dysfunction, and "brain adaptation" will guide drug discovery efforts. This review considers the processes and pathways involved in normal temperature regulation and the impact of fluctuating and declining hormones that result in VMS during the menopausal transition.

Auditory and neurobehavioral effects of exposure to brominated flame retardants in rats—Evaluation of benchmark doses

Ciguatera is a common illness in tropical and subtropical regions that manifests in complex and long-lived symptoms which are more severe in subsequent exposures. This study measures central and peripheral neurologic signs, in parallel with blood toxin levels, in mice exposed once or twice (at 3 days interval) to a sublethal dose of ciguatoxin P-CTX-1 (0.26 ng/g via i.p.). Mice were implanted with radiotransmitters to monitor motor activity and core temperature. A single exposure to ciguatoxin elicited an immediate and transient decrease in motor activity and temperature, and subsequent long-lasting thermoregulatory dysfunction resulting in stabilized body temperature around 36.0 °C with no observable circadian rhythm. The hypothermic response and the reduced activity were enhanced with a second exposure with 30% of the mice dying within 7 h. Measurement of the peripheral nervous system by the tail flick assay revealed increased latency with a single ciguatoxin exposure, and a greater effect following the second exposure. Toxin was measurable in blood up to 3 days following the first exposure; at the 1 h time point the concentrations were significantly elevated after a second exposure. These findings indicate an early response to ciguatoxin manifest in a central response to lower body temperature and reduce motor activity and a more persistent effect on the peripheral system leading to spinal heat antinociception and delayed fever-like response. The greater neurological response to a second ciguatoxin exposure was associated with elevated concentrations of ciguatoxin in the blood solely over the first hour of exposure. In conclusion, a single exposure to toxin exerts a significant neurological response which may be enhanced with subsequent exposure.

The Role of the Selective Serotonin Reuptake Inhibitor Fluoxetine in Temperature Regulation in Ovariectomized Rat Models

Thermoregulation is an integrated network of neuroendocrine, autonomic and somatosensory responses. Thermoregulatory dysfunction occurs during fluctuations or decline of gonadal hormone levels and results in vasomotor symptoms such as hot flushes and/or night-time sweating. The neurotransmitter serotonin (5-HT), has been reported to play a role in thermoregulation via changes in extracellular 5-HT levels and/or activation of various 5-HT receptors. The purpose of this study was to evaluate the role of the selective 5-HT reuptake inhibitor (SSRI), fluoxetine (FLX), on temperature regulation using ovariectomized (OVX) rodent models of thermoregulation. Single, subcutaneous (s.c.) administration of FLX (3, 10, 30 and 60 mg/kg) dose-dependently reduced core body temperature (CBT). FLX at 3 and 10 mg/kg s.c. showed no statistically significant decrease on tail-skin temperature (TST), whereas at higher doses (30 and 60 mg/kg) a significant decrease in TST was noted in the telemetry model. To mimic chronic SSRI treatment, a 5-HT_1A antagonist (WAY-100635; 0.3 mg/kg) was administered 20 min prior to FLX (10 mg/kg). This combination showed no significant improvement on temperature dysfunction compared to FLX alone. Similarly, in a morphine-dependent model of temperature dysfunction FLX, was inactive at 10 mg/kg whereas the 30 and 60 mg/kg s.c. dose abated the naloxone-induced increase in TST by 55 and 81%, respectively. In summary, FLX affected CBT at all doses, but alleviated thermoregulatory dysfunction only at higher doses that are non-selective for the 5-HT system.