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Neuron Aug 2019The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting...
The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
Topics: Animals; Arousal; Buspirone; Circadian Rhythm; Fenclonine; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optogenetics; Quipazine; Raphe Nuclei; Serotonergic Neurons; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sleep; Sleep Deprivation; Tryptophan Hydroxylase; Wakefulness; Zebrafish; Zebrafish Proteins
PubMed: 31248729
DOI: 10.1016/j.neuron.2019.05.038 -
Molecules (Basel, Switzerland) May 2022Agarwood has been used for the administration of hypnotic therapy. Its aromatic scent induces a relaxed state. However, its aromatic constituents and the underlying...
Agarwood has been used for the administration of hypnotic therapy. Its aromatic scent induces a relaxed state. However, its aromatic constituents and the underlying molecular effect are still unclear. This study aims to determine the active substance and molecular mechanism of the hypnotic effect of agarwood essential oil (AEO) incense inhalation in insomniac mice. Insomnia models were induced by para-chlorophenylalanine (PCPA, 300 mg/kg) in mice. The sleep-promoting effect was evaluated. Neurotransmitter levels and its receptor were detected to explore the molecular mechanism. The effective components were analyzed by GC-Q/TOF-MS of AEO. The binding mechanisms of the core compounds and core targets were verified by molecular docking. These results showed that AEO inhalation could significantly shorten sleep latency and prolong sleep time, inhibit autonomous activity and exert good sedative and sleep-promoting effects. A mechanistic study showed that AEO inhalation increased the levels of γ-aminobutyric acid (GABA), the GABA/glutamic acid (Glu) ratio, 5-hydroxytryptamine (5-HT) and adenosine (AD), upregulated the expression levels of GluR1, VGluT1 and 5-HT1A and downregulated 5-HT2A levels. Component analysis showed that the most abundant medicinal compounds were eremophilanes, cadinanes and eudesmanes. Moreover, the docking results showed that the core components stably bind to various receptors. The study demonstrated the bioactive constituents and mechanisms of AEO in its sedative and hypnotic effects and its multicomponent, multitarget and multipathway treatment characteristics in PCPA-induced insomniac mice. These results provide theoretical evidence for insomnia treatment and pharmaceutical product development with AEO.
Topics: Animals; Fenclonine; Gas Chromatography-Mass Spectrometry; Glutamic Acid; Hypnotics and Sedatives; Mice; Molecular Docking Simulation; Oils, Volatile; Serotonin; Sleep Initiation and Maintenance Disorders; gamma-Aminobutyric Acid
PubMed: 35684421
DOI: 10.3390/molecules27113483 -
ACS Sensors Dec 2019Determination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine...
Determination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine accumulates and persists at levels that alter brain development and cause permanent neurological damage and cognitive dysfunction. Recent approaches for treating phenylketonuria focus on injectable medications that efficiently break down phenylalanine but sometimes result in detrimentally low phenylalanine levels. We have identified new DNA aptamers for phenylalanine in two formats, initially as fluorescent sensors and then, incorporated with field-effect transistors (FETs). Aptamer-FET sensors detected phenylalanine over a wide range of concentrations (fM to mM). -Chlorophenylalanine, which inhibits the enzyme that converts phenylalanine to tyrosine, was used to induce hyperphenylalaninemia during brain development in mice. Aptamer-FET sensors were specific for phenylalanine versus -chlorophenylalanine and differentiated changes in mouse serum phenylalanine at levels expected in patients. Aptamer-FETs can be used to investigate models of hyperphenylalanemia in the presence of structurally related enzyme inhibitors, as well as naturally occurring amino acids. Nucleic acid-based receptors that discriminate phenylalanine analogs, some that differ by a single substituent, indicate a refined ability to identify aptamers with binding pockets tailored for high affinity and specificity. Aptamers of this type integrated into FETs enable rapid, electronic, label-free phenylalanine sensing.
Topics: Animals; Aptamers, Nucleotide; DNA; Electrochemical Techniques; Fenclonine; Mice; Phenylalanine; Phenylketonurias; Transistors, Electronic
PubMed: 31631652
DOI: 10.1021/acssensors.9b01963 -
Scientific Reports Feb 2021Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined...
Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.
Topics: Analgesics, Opioid; Anemia, Sickle Cell; Animals; Chronic Pain; Diet; Disease Models, Animal; Duloxetine Hydrochloride; Female; Fenclonine; Hyperalgesia; Interpersonal Relations; Male; Mice; Mice, Transgenic; Morphine; Serotonin; Serotonin Antagonists; Serotonin and Noradrenaline Reuptake Inhibitors; Signal Transduction; Spinal Cord
PubMed: 33526805
DOI: 10.1038/s41598-021-81654-1 -
British Medical Journal (Clinical... Oct 1983Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a...
Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a periembolisation regimen of cyproheptadine, fenclonine, aprotinin, methylprednisolone, tobramycin, flucloxacillin, and metronidazole. Embolisation was not performed in one patient with an occluded portal vein and was unsatisfactory in two others, in one because she was moribund and in the other because the hepatic artery had been ligated. Dramatic improvement in symptoms occurred in the nine patients in whom embolisation was successfully carried out, with abolition of flushing, severe abdominal pain, and wheeze and reduction in diarrhoea from 10.5 (SD 7.6) to 1.6 (0.9) stools/day. Urinary excretion of 5-hydroxyindole acetic acid fell from 1048 (716) to 289 (184) mumol/24 h (200 (137) to 55 (35) mg/24 h). Complications included one death from septicaemia, a hepatic abscess requiring surgical drainage, abdominal pain in three patients, pleural effusion in two, and transient encephalopathy in one. Relief of symptoms lasted for one to 24 months, and second embolisation in two patients produced further remissions of four to six months. Five patients died, one to 40 months after embolisation, in four cases because of metastases or heart failure. Hepatic embolisation is the treatment of choice for symptoms of the carcinoid syndrome resistant to medical treatment.
Topics: Adult; Aged; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Time Factors
PubMed: 6412893
DOI: 10.1136/bmj.287.6397.932 -
Forensic Science International May 2024Since its first employment in World War I, chlorine gas has often been used as chemical warfare agent. Unfortunately, after suspected release, it is difficult to prove...
Since its first employment in World War I, chlorine gas has often been used as chemical warfare agent. Unfortunately, after suspected release, it is difficult to prove the use of chlorine as a chemical weapon and unambiguous verification is still challenging. Furthermore, similar evidence can be found for exposure to chlorine gas and other, less harmful chlorinating agents. Therefore, the current study aims to use untargeted high resolution mass spectrometric analysis of chlorinated biomarkers together with machine learning techniques to be able to differentiate between exposure of plants to various chlorinating agents. Green spire (Euonymus japonicus), stinging nettle (Urtica dioica), and feathergrass (Stipa tenuifolia) were exposed to 1000 and 7500 ppm chlorine gas and household bleach, pool bleach, and concentrated sodium hypochlorite. After sample preparation and digestion, the samples were analyzed by liquid chromatography high resolution tandem mass spectrometry (LC-HRMS/MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS). More than 150 chlorinated compounds including plant fatty acids, proteins, and DNA adducts were tentatively identified. Principal component analysis (PCA) and linear discriminant analysis (LDA) showed clear discrimination between chlorine gas and bleach exposure and grouping of the samples according to chlorine concentration and type of bleach. The identity of a set of novel biomarkers was confirmed using commercially available or synthetic reference standards. Chlorodopamine, dichlorodopamine, and trichlorodopamine were identified as specific markers for chlorine gas exposure. Fenclonine (Cl-Phe), 3-chlorotyrosine (Cl-Tyr), 3,5-dichlorotyrosine (di-Cl-Tyr), and 5-chlorocytosine (Cl-Cyt) were more abundantly present in plants after chlorine contact. In contrast, the DNA adduct 2-amino-6-chloropurine (Cl-Ade) was identified in both types of samples at a similar level. None of these chlorinated biomarkers were observed in untreated samples. The DNA adducts Cl-Cyt and Cl-Ade could clearly be identified even three months after the actual exposure. This study demonstrates the feasibility of forensic biomarker profiling in plants to distinguish between exposure to chlorine gas and bleach.
Topics: Chlorine; Biomarkers; Principal Component Analysis; Chromatography, Liquid; Discriminant Analysis; Tandem Mass Spectrometry; Sodium Hypochlorite; DNA Adducts; Disinfectants; Chemical Warfare Agents; Fatty Acids; Plant Proteins
PubMed: 38615427
DOI: 10.1016/j.forsciint.2024.112022 -
Behavioural Brain Research Feb 2020The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker,...
Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.
The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl--p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro--phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.
Topics: Age Factors; Animals; Behavior, Animal; Central Nervous System Stimulants; Cocaine; Dextroamphetamine; Dopamine Agents; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Female; Fenclonine; Ketamine; Locomotion; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Serotonin Agents; alpha-Methyltyrosine
PubMed: 31655095
DOI: 10.1016/j.bbr.2019.112302 -
Journal of Traditional Chinese Medicine... Aug 2023To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and...
Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.
OBJECTIVE
To investiage the effect of electroacupuncture (EA) at a single acupoint of Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) and at combined acupoints of Shenmen (HT7) and Baihui (GV20) and Sanyinjiao (SP6) on the PKA/CREB and BDNF/TrkB signaling, as well as neuroapoptosis and neurogenesis in hippocampus and elucidate the underlying mechanism of single and combined acupoints on ameliorating spatial learning and memory deficits in a rat model of primary insomnia.
METHODS
Primary insomnia was modeled by intraperitoneal injection of para-chlorophenylalanine (PCPA) once daily for 2 d. EA was applied at Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), or Shenmen (HT7) + Baihui (GV20) + Sanyinjiao (SP6) (combined) for 30 min daily for 4 d. Spatial learning and memory function was evaluated by the Morris water maze (MWM) test. Protein expressions of hippocampal cAMP-dependent protein kinase (PKA)-Cβ, phosphorylated cAMP-responsive element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor B (TrkB) were evaluated by Western blotting. Neuronal apoptosis in the hippocampus was detected with the transferase-mediated dUTP-X nick end labeling assay. Endogenous neurogenesis was examined with bromodeoxyuridine staining. The MWM test and hippocampal p-CREB, BDNF, and TrkB protein levels in the combined acupoints group were evaluated after the administration of a PKA-selective inhibitor (H89).
RESULTS
Spatial learning and memory were significantly impaired in rats with insomnia. The spatial learning deficits were ameliorated in the Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6), and combined groups; this improvement was significantly greater in the combined group than the single acupoint groups. The spatial memory impairment was improved in the combined, Baihui (GV20), and Shenmen (HT7) groups, but not the Sanyinjiao (SP6) group. The expressions of PKA-Cβ, p-CREB, BDNF, and TrkB were decreased in rats with insomnia. All these proteins were significantly upregulated in the combined group. PKA/p-CREB protein levels were elevated in the Baihui (GV20) and Shenmen (HT7) groups, whereas BDNF/TrkB expression was upregulated in the Sanyinjiao (SP6) group. The staining results showed significant attenuation of hippocampal cell apoptosis and increased numbers of proliferating cells in the combined group, whereas the single acupoint groups only showed decreased numbers of apoptotic cells. In the combined group, the PKA inhibitor reversed the improvement of spatial memory and upregulation of p-CREB expression caused by EA, but did not affect its activation of BDNF/TrkB signaling.
CONCLUSIONS
EA at the single acupoints Baihui (GV20), Shenmen (HT7), or Sanyinjiao (SP6) had an ameliorating effect on the spatial learning and memory deficits induced by insomnia. EA at combined acupoints exerted a synergistic effect on the improvements in spatial learning and memory impairment in rats with insomnia by upregulating the hippocampal PKA/CREB and BDNF/TrkB signaling, facilitating neurogenesis, and inhibiting neuronal apoptosis. These findings indicate that EA at combined acupoints [(Baihui (GV20), Shenmen (HT7), and Sanyinjiao (SP6)] achieves a more pronounced regulation of hippocampal neuroplasticity than EA at single acupoints, which may partly explain the underlying mechanisms by which EA at combined acupoints exerts a better ameliorative effect on the cognitive dysfunction caused by insomnia.
Topics: Rats; Animals; Rats, Sprague-Dawley; Electroacupuncture; Brain-Derived Neurotrophic Factor; Acupuncture Points; Sleep Initiation and Maintenance Disorders; Fenclonine; Spatial Learning; Hippocampus
PubMed: 37454255
DOI: 10.19852/j.cnki.jtcm.20230308.001 -
Zhongguo Yao Li Xue Bao = Acta... Nov 1995To study the effect of serotonin (5-HT) on pain modulation of substance P (SP) in spinal cord of rats.
AIM
To study the effect of serotonin (5-HT) on pain modulation of substance P (SP) in spinal cord of rats.
METHODS
Using immunohisto-chemistry and measurement of pain threshold.
RESULTS
The c-fos expression evoked by intrathecal injection (it) SP 10 micrograms and sc 5% formaldehyde (For) 150 microL in the hindpaw was densely distributed in the laminae I, II, V, and VI of spinal dorsal horn. The pain threshold in the SP group was decreased while the pain intensity rating measured by behavioral method in the For group was increased. The c-fos expression induced by it 5-HT 20 micrograms was mostly distributed in the spinal dorsal horn in laminae III-IV and the pain threshold was increased. SP and For induced c-fos expressions in the spinal cord and the pain responses were reduced by 5-HT and increased by 5-HT depletor fenclonine 300 mg.kg-1.
CONCLUSION
SP mainly played an algogenesia in the spinal cord. 5-HT inhibited the c-fos expression in the spinal cord evoked by SP and participated in pain modulation of SP.
Topics: Animals; Female; Genes, fos; Male; Pain Threshold; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Serotonin; Serotonin Receptor Agonists; Spinal Cord; Substance P
PubMed: 8732045
DOI: No ID Found -
Molecules (Basel, Switzerland) Jan 2023To study the extraction process of agarwood active ingredients (AA) and investigate the safety and effectiveness of AA in the treatment of insomnia rats by nasal...
OBJECTIVE
To study the extraction process of agarwood active ingredients (AA) and investigate the safety and effectiveness of AA in the treatment of insomnia rats by nasal administration.
METHOD
A β-cyclodextrin (β-CD) inclusion compound (a-β-CD) was prepared from agarwood essential oil (AEO), and the preparation process was optimized and characterized. The safety of AA in nasal mucosa was evaluated through maxillary mucosa and rat nasal mucosa models. Insomnia animal models were replicated by injecting -chlorophenylalanine (PCPA), conducting behavioral tests, and detecting the expression levels of monoamine neurotransmitters (NE and 5-HT) and amino acids (GABA/Glu) in the rat hypothalamus.
RESULTS
The optimum inclusion process conditions of β-CD were as follows: the feeding ratio was 0.35:1.40 (g:g), the inclusion temperature was 45 °C, the inclusion time was 2 h, and the ICY% and IEO% were 53.78 ± 2.33% and 62.51 ± 3.21%, respectively. The inclusion ratio, temperature, and time are the three factors that have significant effects on the ICY% and IEO% of a-β-CD. AA presented little damage to the nasal mucosa. AA increased the sleep rate, shortened the sleep latency, and prolonged the sleep time of the rats. The behavioral test results showed that AA could ameliorate depression in insomnia rats to a certain extent. The effect on the expression of monoamine neurotransmitters and amino acids in the hypothalamus of rats showed that AA could significantly reduce NE levels and increase the 5-HT level and GABA/Glu ratio in the hypothalamus of insomnia rats.
CONCLUSION
The preparation of a-β-CD from AEO can reduce its irritation, improve its stability, increase its curative effect, and facilitate its storage and transport. AA have certain therapeutic effects on insomnia. The mechanism of their effect on rat sleep may involve regulating the expression levels of monoamine neurotransmitters and amino acids in the hypothalamus.
Topics: Animals; Rats; Cyclodextrins; Fenclonine; gamma-Aminobutyric Acid; Neurotransmitter Agents; Oils, Volatile; Serotonin; Sleep Initiation and Maintenance Disorders
PubMed: 36677694
DOI: 10.3390/molecules28020635