Melatonin Enhances Object Recognition Memory through Melatonin MT1 and MT2 Receptor-Mediated and Non-Receptor-Mediated Mechanisms in Male Mice

Melatonin (MEL) has been reported to have acute enhancing effects on some aspects of cognition. Recently, we revealed that N1-acetyl-5-methoxyquinuramine (AMK), a brain metabolite of MEL, is much more potent than MEL in converting short-term memory (STM) to long-term memory (LTM) with a single administration immediately after the acquisition trial of the novel object recognition (NOR) task. These data suggest that the memory-enhancing effects of MEL may be mediated by mechanisms independent of the activation of MEL MT1 and MT2 receptors. In the present study, we examined the contribution of MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms to the acute memory-enhancing effects of MEL using NOR task. Mice were administered with either MEL, AMK, or a highly selective MT1/MT2 receptor agonist ramelteon (RAM) immediately after the acquisition trial and the effects of varying doses of these drugs on both STM and LTM performance were compared. We found that both AMK and RAM were more potent than MEL in both facilitating STM and promoting LTM formation. We also found that pretreatment with luzindole, a MT1/MT2 receptor antagonist, markedly suppressed only the effects of RAM. These results suggest that acutely administered MEL enhances NOR memory through both MT1 and MT2 receptor-mediated and non-receptor-mediated mechanisms.

Changes of melatonin and its receptors in synchronizing turbot(Scophthalmus maximus)seasonal reproduction and maturation rhythm

In most fish,reproduction is seasonal or periodic under the suitable conditions.In turbot(Scophthalmus maximus)farms,one of the most economically important marine flatfish species,changes in daylength could cause changes in the spawning time.In this study,to characterize the regulation of reproductive physiology following light signals,three melatonin receptors(Mtnr)investigated in turbot were named sm Mtnr1,sm Mtnr2,and sm Mtnr1 c.Distinct expression profiles demonstrated that Mtnr m RNAs were concentrated in the brain(as detected in the hypothalamus(Hy)and mesencephalon(Me)),gonad and eye.The most abundant Mtnr1 and Mtnr2 m RNA expression levels were detected in the central nervous system at the beginning of the breeding season,suggesting that Mtnr1 and Mtnr2 may play vital roles in the regulation of turbot gonadal development.In addition,the melatonin profiles gradually increased and reached to the highest level at the spawning stage,indicating that melatonin is a potent hormone in the regulation of fish oocyte growth and maturation.The results of this study suggested that melatonin is the primary factor that transduces the light signal and regulates the physiological functions of turbot seasonal reproduction.Moreover,the results of this study may establish a foundation for further research seeking to identify fish melatonin receptors involved in the gonadal development and gamete maturation.

Hepatoprotective actions of melatonin:Possible mediation by melatonin receptors

Melatonin,the hormone of darkness and messenger of the photoperiod,is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone's intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo,and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis,hemorrhagic shock,ischemia/reperfusion,and in numerous models of toxic liver injury. Melatonin's influence on hepatic antioxidant enzymes and other potentially relevant pathways,such as nitric oxide signaling,hepatic cytokine and heat shock protein expression,are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection,this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.

Melatonin Receptors Agonistic Activities of Phenols from Gastrodia elata

Gastrodia elata is a famous traditional Chinese herb with medicinal and edible application.In this study,three new polybenzyls,gastropolybenzylols G-I(1-3)were isolated from the EtOAc extract of G.elata.Their structures were identified by extensive spectroscopic analyses involving HRESIMS,UV,IR,1D and 2D NMR.Compound 1 showed agonistic effects on MT1 and MT_(2) receptors with agonistic rates of 55.91±4.84%and 165.13±5.65%at the concentration of 0.5 mM,respectively,and an EC_(50) value of 76.24μM on MT_(2) receptor.

UFLC‑PDA‑MS/MS Profling of Seven Uncaria Species Integrated with Melatonin/5‑Hydroxytryptamine Receptors Agonistic Assay

Uncariae Ramulus Cum Uncis(Gou-Teng),the dried hook-bearing stems of several Uncaria plants(Rubiaceae),is a wellknown herbal medicine in China.The clinical application of Gou-Teng is bewildered for the morphological and chemical similarity between diferent species.In order to discern their chemical and biological diference,an ultra-fast liquid chromatography equipped with ion trap time-of-fight mass spectrometry(UFLC-IT/TOF-MS)combining with melatonin(MT1 and MT2)and 5-hydroxytryptamine(5-HT1A and 5-HT2C)receptors agonistic assay in vitro was conducted on seven Uncaria species.As a result,57 compounds including 35 indole alkaloids,ten favonoids,fve triterpenoids,fve chlorogenic analogues,and two other compounds were characterized based on their MS/MS patterns and UV absorptions.Specifcally,cadambine-type and corynanthein-type alkaloids were exclusively present in U.rhynchophylla and U.scandens,whereas corynoxine-type alkaloids were commonly detected in all the seven Uncaria plants.Three Uncaria species,U.rhynchophylla,U.macrophylla,and U.yunnanensis showed obviously agnostic activity on four neurotransmitter receptors(MT1,MT2,5-HT1A,and 5-HT_(2C)).This frst-time UFLCMS-IT-TOF analyses integrated with biological assay on seven Uncaria plants will provide scientifc viewpoints for the clinical application of Gou-Teng.

Distribution of melatonin receptor in human fetal brain

Objective:To studythedistributionof2kindsof melatoninreceptorsubtypes(mt1andMT2)in humanfetal brain.Methods:Thefetalbraintissueswereslicedandthedistributionof melatoninreceptorsinhumanfetalbrainwere detectedusingimmunohistochemistryandin situ hybridization.Results:Melatoninreceptormt1existedinthecerebellum andhypothalamus,melatoninreceptorMT2existsinhypothalamus,occipitalandmedulla.Conclusion:Two kindsof melatoninreceptors,mt1andMT2existinthemembraneandcytosolof braincells,indicatingthathumanfetalbrainis a targetorganof melatonin.

Seasonal photoperiodic influence of pineal melatonin on hypothalamic-pituitary-adrenal axis-hippocampal-receptor in male rats

Background: Based on the effect of seasonal changes on human visceral function, this study investigated the impact of seasonal photoperiod of the pineal body on hypothalamic-pituitary-adrenal axis-hippocampal-receptor in rats, aiming to reveal the mechanism by which pineal gland melatonin regulates the seasonal secretion of hippocampal neurotransmitters.Methods: Vernal equinox, summer solstice, autumn equinox, and winter solstice were selected as four experimental time points, and rats were randomly divided into normal control group, sham operation group, and pinealectomized group. The seasonal changes in corticotropin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH), corticosterone, hypothalamic melatonin receptor(MTR), and hippocampal corticosterone receptor(CORTR) were examined by enzyme-linked immunosorbent assay.Results: Comparing the same group between different seasons, we showed that in the normal control group, CRH, ACTH, corticosterone, and MTR were higher, while CORTR was lower in autumn and winter than in spring(all P <.05). Compared with the normal control group, the pinealectomized group showed higher levels of corticosterone(P =.01), MTR(P =.01), and CORTR(P =.03) during spring;reduced levels of MTR and CORTR(both P <.001) during summer;higher levels of ACTH(P =.001) and MTR(P <.001),and lower levels of CRH(P =.001), corticosterone(P <.001), and CORTR(P =.003) during autumn;and lower levels of CRH(P <.001) and MTR(P =.004), and higher level of ACTH(P <.001) in winter.Conclusions: Seasonal photoperiod acts on the pineal gland to secrete different levels of melatonin,resulting in seasonal changes in the hypothalamic-pituitary-adrenal axis-hippocampal-receptor, which may be the pathophysiological basis for the onset of seasonal affective disorder.

Antinociceptive effects of novel melatonin receptor agonists in mouse models of abdominal pain

AIM: To characterize the antinociceptive action of the novel melatonin receptor(MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain. METHODS: Visceral pain was induced by intracolonic(ic) application of mustard oil or capsaicin solution or by intraperitoneal(ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, thenon-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly(icv) prior to the induction of pain. RESULTS: Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracerebroventricularly, but not ip administration of luzindole or 4-P-PDOT blocked the antinociceptive actions of Neu-P11 or Neu-P12. CONCLUSION: Neu-P12 produced the most potent and long-lasting antinociceptive effect. Further development of Neu-P12 for future treatment of abdominal pain seems promising.

Research Progress on the Function of Melatonin and Its Receptor in Animal Reproduction

Melatonin has been a research hotspot in the field of medicine and life sciences for more than 60 years since it was discovered.In order to accelerate the increase of economic animal productivity,a large number of studies also have focused on the regulation of melatonin and its receptors during animal reproduction in recent years.In this paper,the relevant characteristics of melatonin and the latest research progress in animal reproduction were discussed,and the biological functions of melatonin were reviewed from the aspects of germ cells,reproductive endocrine and embryo development,laying a theoretical foundation for further exploring the regulation mechanism of melatonin on reproductive process.

Possible Role of Exogenous Melatonin and Melatonin-Receptor-Agonists in the Treatment of Menopause―Associated Sleep Disturbances

One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms and changing reproductive hormone levels, circadian rhythm abnormalities, primary insomnia, mood disorders, coexistent medical conditions, and lifestyle. Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs with prolonged effects and slow-release melatonin preparations have been developed. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression associated insomnia. This article presents the currently available evidence regarding the effects of these compounds on sleep quality and their possible use in menopause associated sleep disturbances.

Comparison of the Melatonin Receptor Agonist Ramelteon and the Non-Benzodiazepine Hypnotic Zolpidem for Nocturia

To examine the efficacy of the melatonin receptor agonist ramelteon for nocturia, it was compared with zolpidem, a conventional non-benzodiazepine hypnotic. A total of 50 patients with nocturia (32 urinations/night) were enrolled. Subjects assigned odd numbers or even numbers were respectively prescribed 8 mg of ramelteon (n = 27;mean age: 75 years) or 5 mg of zolpidem (n = 23;mean age: 73 years) once a day before sleeping for 4 weeks. The daytime and nighttime frequencies of urination, as well as the results of global self-assessment by the patients, were compared between the two groups before and after 4 weeks of treatment. Both ramelteon and zolpidem caused a significant decrease of nocturia to about once per night after 4 weeks. The global self-assessment rating at 4 weeks was “good” or “fair” for more patients in the zolpidem group than in the ramelteon group, while the rating was “excellent” or “no change” for more patients in the ramelteon group. There were no serious adverse events in either group. Ramelteon was safe and effective for nocturia, achieving similar results to zolpidem. However, responders and non-responders to ramelteon were more clearly distinguished. Ramelteon might be effective for patients with sleep disturbance and nocturia because of low melatonin levels. Therefore, as diagnostic therapy for identification of nocturia caused by sleep disturbance and melatonin deficiency, ramelteon should be administered to patients who do not respond to alpha-1 antagonists and/or anticholinergic agents.

P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients:A matter of disease activity?

BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2DM.Various considerations can make selecting and switching between different GLP-1 RAs challenging.Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model

Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.

2-Iodomelatonin上调NRF2表达对缺血性脑损伤神经保护作用

目的探讨褪黑激素受体1(MT1)激动剂2-Iodomelatonin通过上调核因子E2相关因子2(NRF2)对大脑中动脉栓塞小鼠的神经保护作用。方法采用大脑中动脉栓塞(MCAO)法制备小鼠缺血性脑损伤体内模型,给予2-Iodomelatonin及NRF2抑制剂(Nrf2-IN-1)干预。采用三苯基氯化四氮唑(TTC)染色法检测小鼠大脑的梗死体积,Western Blot法检测缺血损伤后大脑皮质半暗带NRF2表达水平,改良神经功能缺损程度评分(mNSS)评估2-Iodomelatonin和Nrf2-IN-1干预对小鼠缺血性脑损伤亚急性期运动功能的影响。结果TTC染色结果显示,2-Iodomelatonin干预可以显著降低缺血性脑损伤小鼠的大脑梗死体积(F=7.79,q=5.06,P<0.05)。Western Blot结果显示,2-Iodomelatonin干预可上调小鼠皮质梗死半暗带NRF2的表达水平(F=10.56,q=3.99,P<0.05)。mNSS评分结果显示,2-Iodomelatonin干预可以显著改善缺血性脑损伤第14天的运动功能损伤(F=6.12,q=4.79,P<0.05),该效应可被Nrf2-IN-1逆转(q=3.60,P<0.05)。结论2-Iodomelatonin干预可以通过上调NRF2降低缺血性脑损伤小鼠的大脑梗死体积并改善14 d时的运动功能损伤。