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To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.
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Membrana Mucosa , Antagonistas Muscarínicos , Receptores Muscarínicos , Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Humanos , Antagonistas Muscarínicos/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/orina , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/efectos de los fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Adulto , AncianoRESUMEN
The analysis of ascorbic acid using the 2,6-dichloroindophenol (DCIP) titration method is a well-established technique, but requires the skilled handling of a burette for accurate measurements. In the present study, we propose a modified DCIP titrimetric method that replaces the burette with a dropper and employs an electronic balance to measure the titrated amount by weight. The dropper used can be flexibly selected, allowing for a wide range of drop sizes, from large to very small. This modification offers several advantages, including lower skill requirements, a 43% reduction in the analysis time, a 50% decrease in sample/reagent consumption, and the ability to prepare DCIP standard solutions tailored to the concentration of ascorbic acid in the sample being analyzed. Our analysis of several food samples using this improved method showed that inherent issues of the DCIP method, such as determining the titration end point, could not be resolved. Nevertheless, the improved titration method remains more convenient and adaptable than the original approach using a burette, enabling quick and accurate analysis, especially for unskilled analysts.
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Ácido Ascórbico , Electrónica , IndofenolRESUMEN
Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly. Geriatr Gerontol Int 2024; 24: 81-87.
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Antagonistas Colinérgicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Anciano , Antagonistas Colinérgicos/efectos adversos , Preparaciones Farmacéuticas , PolifarmaciaRESUMEN
AIM: The present study aimed to develop a pharmacological evidence-based anticholinergic burden scale (ABS) through a direct assessment of muscarinic receptor-binding activities of 260 medications commonly used in older adults. METHODS: The muscarinic receptor-binding activities of 260 drugs were assessed by the displacement of specific [N-methyl-3 H]scopolamine methyl chloride binding in the rat brain. The maximum blood concentrations (Cmax ) of drugs after their administration to subjects were cited from their interview forms. RESULTS: In total, 96 of 260 drugs displayed concentration-dependent muscarinic receptor binding in rat brain. Based on muscarinic receptor-binding activity (IC50 ) and Cmax after the administration at clinical doses in humans, we rated ABS 3 (strong) for 33 drugs and ABS 2 (moderate) for 37 drugs. There was an approximate similarity between muscarinic receptor-binding activities (IC50 ) and Cmax of 33 drugs (ABS 3) after their administration at clinical doses in humans. Furthermore, 26 drugs were defined as ABS 1 (weak) by muscarinic receptor-binding activity. The remaining 164 drugs exhibited slight or no significant muscarinic receptor-binding activities at high concentration of 100 µM, and they were defined as ABS 0. There was a marked similarity for 28 drugs (ABS 3) between the present ABS data and their previous scoring data in the literature. CONCLUSIONS: To our knowledge, the present study developed the first comprehensive pharmacological evidence-based ABS of drugs based on muscarinic receptor-binding activity, which provides guidance as to which drugs may be discontinued to reduce anticholinergic burden. Geriatr Gerontol Int 2023; 23: 558-564.
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Antagonistas Colinérgicos , Escopolamina , Humanos , Ratas , Animales , Anciano , Antagonistas Colinérgicos/uso terapéutico , Receptores Muscarínicos/metabolismoRESUMEN
Atopic dermatitis is a common chronic inflammatory skin disease, with most cases experiencing skin barrier dysfunction and enhanced allergen entry, accompanied by cytokine production which evokes predominantly type-2-skewed immune responses, itch, and scratching behavior. Although intense itch and excessive scratching behavior affect progression of skin lesions, it is unclear what causes them. Data suggest that scratching behavior stimulates brain dopaminergic reward and habit learning systems, strengthening habitual scratching behavior, while nocturnal scratching behavior presumably increases locus coeruleus-noradrenergic system activity, prompting sleep disturbances. At the early stage of atopic dermatitis, increased cortisol levels, due to hypothalamic-pituitary-adrenal axis overactivation caused by such system stimulation, can induce dorsolateral prefrontal cortex disturbance with reinforcement of habitual scratching behavior and may aggravate type-2-skewed immune responses in the skin. During the later phases, whereas blunted hypothalamic-pituitary-adrenal axis function and the shift of type-2-dominated to type-1-co-dominated inflammation are induced, noradrenergic system overactivation-associated dorsolateral prefrontal cortex disruption is ongoing and responsible for itch cognitive distortion to catastrophize about itch, which leads to a vicious spiral along with habitual scratching behavior and skin lesions. Data are presented in this review indicating that while skin immune system dysfunction initiates pathologic changes in atopic dermatitis, brain neural network and stress system alterations can promote the progression of this condition. It is also suggested that cognitive distortion contributes to pathology in atopic dermatitis as with some psychiatric disorders and chronic pain. The proposed mechanistic model could lead to development of novel medications for slowing or terminating the relentless progression of this disorder. SIGNIFICANCE STATEMENT: Although conventional pharmacological interventions focusing on skin homeostasis and itch occurrence significantly attenuate clinical signs in atopic dermatitis patients, achievement of 100% improvement is less than 40% in several double-blind, randomized, placebo-controlled trials. Our model predicts that itch cognitive distortion, due to dorsolateral prefrontal cortex disturbance, can significantly contribute to the progression of atopic dermatitis and that agents capable of improving brain neural network, stress system, and skin homeostasis may be effective as interventions in the treatment of this condition.
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Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Sistema Hipotálamo-Hipofisario/patología , Sistema Hipófiso-Suprarrenal/patología , Prurito/etiología , Encéfalo/patología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
While alterations in the locus coeruleus-noradrenergic system are present during early stages of neuropsychiatric disorders, it is unclear what causes these changes and how they contribute to other pathologies in these conditions. Data suggest that the onset of major depressive disorder and schizophrenia is associated with metal dyshomeostasis that causes glial cell mitochondrial dysfunction and hyperactivation in the locus coeruleus. The effect of the overactive locus coeruleus on the hippocampus, amygdala, thalamus, and prefrontal cortex can be responsible for some of the psychiatric symptoms. Although locus coeruleus overactivation may diminish over time, neuroinflammation-induced alterations are presumably ongoing due to continued metal dyshomeostasis and mitochondrial dysfunction. In early Alzheimer's and Parkinson's diseases, metal dyshomeostasis and mitochondrial dysfunction likely induce locus coeruleus hyperactivation, pathological tau or α-synuclein formation, and neurodegeneration, while reduction of glymphatic and cerebrospinal fluid flow might be responsible for ß-amyloid aggregation in the olfactory regions before the onset of dementia. It is possible that the overactive noradrenergic system stimulates the apoptosis signaling pathway and pathogenic protein formation, leading to further pathological changes which can occur in the presence or absence of locus coeruleus hypoactivation. Data are presented in this review indicating that although locus coeruleus hyperactivation is involved in pathological changes at prodromal and early stages of these neuropsychiatric disorders, metal dyshomeostasis and mitochondrial dysfunction are critical factors in maintaining ongoing neuropathology throughout the course of these conditions. The proposed mechanistic model includes multiple pharmacological sites that may be targeted for the treatment of neuropsychiatric disorders commonly.
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Trastorno Depresivo Mayor , Enfermedades Neurodegenerativas , Humanos , Locus Coeruleus/metabolismo , Trastorno Depresivo Mayor/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Norepinefrina/metabolismo , Homeostasis , Mitocondrias/metabolismoRESUMEN
Marine foods can be contaminated with organochlorines and the risk to human beings who consume these foods needs to be evaluated. We examined the teratogenic effects of contaminants extracted from whale bacon on rat embryos using a whole-embryo culture system. Embryonic day 11.5 embryos were cultured for 48 h with organohalogens extracted from whale bacon at low (polychlorinated biphenyls (PCBs): 0.32 ppm, dichlorodiphenyltrichloroethanes (DDTs): 0.16 ppm, chlordanes (CHLs): 0.02 ppm) and high (PCBs: 2.15 ppm, DDTs: 1.99 ppm, CHLs: 0.20 ppm) doses. The levels of organohalogen compounds in cultured embryos were determined. The organochlorine contaminants extracted from whale products were readily transferred to the cultured rat embryos. The number of heartbeats, yolk sac circulation score, and embryonic body circulation score of embryos did not change during the culture period in either exposure group. Cultured embryos treated with the low-dose contaminated medium for 48 h showed abnormalities of the mandible, and craniofacial or forelimb hematomas with an incidence of 50%. All embryos treated with the high-dose medium showed craniofacial abnormalities and cleft lip, and limb abnormalities and hematomas. These results indicate that the organohalogen contaminants in whale bacon may be teratogenic in a dose-dependent manner. Further studies are necessary to determine the dose-effect relationship.
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Hidrocarburos Clorados , Bifenilos Policlorados , Carne de Cerdo , Animales , Clordano , Hematoma , Humanos , Hidrocarburos Clorados/toxicidad , Bifenilos Policlorados/toxicidad , Ratas , BallenasRESUMEN
Saw palmetto berry extract (SPE) is the most commonly consumed supplement by men with benign prostatic hyperplasia (BPH). The oral administration of SPE was previously shown to significantly attenuate urodynamic symptoms in the hyperactive bladders of female rats by increasing bladder capacity and prolonging the micturition interval. The amelioration of urodynamic symptoms by SPE may be partly attributed to its binding to muscarinic receptors in the urinary bladder and its inhibition of vanilloid receptors on afferent nerves. Therefore, SPE may be pharmacologically effective at mitigating lower urinary tract symptoms (LUTS) in women. The efficacy and safety of a 12-week treatment with SPE in adult women with urinary symptoms were examined herein. The daytime frequency score in the core lower urinary symptom score (CLSS) questionnaire was significantly lower in women with LUTS treated with SPE for 12 weeks than in the placebo group. A subgroup analysis revealed that SPE alleviated the symptoms of daytime frequency (CLSS Q1) and nocturia (CLSS Q2) in a subset of subjects with a CLSS Q5 score of 1 or higher. The daytime frequency of urination in overactive bladder symptom score (OABSS) Q1 was also significantly improved by the SPE treatment. In conclusion, the present study is the first to demonstrate the potential of SPE to mitigate LUTS in adult women.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Animales , Femenino , Humanos , Japón , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Ratas , SerenoaRESUMEN
The present study aimed to characterize and compare ß-adrenoceptors in the rat bladder with those in the heart and lungs of SD rats (8-10 weeks old) using subtype-selective agonists and antagonists in a radioligand binding assay with (-)-[125I]cyanopindolol ([125I]CYP), and also to clarify alterations in ß-adrenoceptors in the bladder of spontaneously hypertensive rats (SHR) at 14 weeks old, from those of Wistar-Kyoto rats (WKY) and Wistar rats at the same age. A radioligand binding assay with [125I]CYP was used to measure ß-adrenoceptor binding activity in rat tissues. Metoprolol exhibited the highest affinity to specific binding sites of [125I]CYP in the rat heart, indicating the dominance of ß1-adrenoceptors. ß3-selective agonists (BRL37344 and CL316243) and antagonist (SR59230A) exhibited higher affinity to specific binding sites of [125I]CYP in the bladder than in the heart and lungs. Furthermore, the binding affinity of the ß2-selective antagonist, ICI118551 was the highest in the bladder. The Bmax of specific [125]CYP binding in the bladder was significantly lower in WKY and SHR than in Wistar rats. The present study provides further evidence for the coexistence of ß2-and ß3-adrenoceptors in the rat bladder, and indicates that ß-adrenoceptor density is lower in the bladders of WKY and SHR.
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Pulmón/metabolismo , Miocardio/metabolismo , Ratas Endogámicas SHR/metabolismo , Receptores Adrenérgicos beta/metabolismo , Vejiga Urinaria/metabolismo , Animales , Ensayo de Unión Radioligante/métodos , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Ratas Wistar , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
OBJECTIVE: Transient receptor potential vanilloid subtype 1 (TRPV1) may play a significant role in the pathophysiology of the bladder. The present study investigated the effects of the herbal product, saw palmetto extract (SPE) on TRPV1-mediated Ca2+ influx and specific [3 H]resiniferatoxin ([3 H]RTX) binding to TRPV1 in HEK293 cells expressing TRPV1 (HEK293VR11 cells). METHODS: Ca2+ influx induced by and the direct binding activity of TRPV1 were measured using a method with Fura 2-AM, a cytoplasmic calcium indicator, and a radioligand binding assay using a [3 H]RTX, respectively. RESULTS: SPE did not markedly affect Ca2+ influx in HEK293VR11 cells; however, it significantly inhibited capsaicin-induced increases in Ca2+ influx in these cells. The specific binding of [3 H]RTX in HEK293VR11 cells was saturable with Kd value of 120 ± 7 pM and Bmax of 1.07 ± 0.10 fmol/mg protein, and was inhibited by low concentrations of non-labeled RTX with Ki of 60.1 ± 7.6 nM. These results confirmed the pharmacological specificity of specific binding sites of [3 H]RTX to TRPV1 in HEK293VR11 cells. SPE inhibited the specific binding of [3 H]RTX in a concentration-dependent manner, with Ki of 24.2 ± 1.4 µg/mL. CONCLUSIONS: The present study demonstrated for the first time, that SPE inhibited capsaicin-induced Ca2+ influx with binding to TRPV1 in HEL293VR11 cells. These results will contribute to a more detailed understanding of the pharmacological effects of SPE on urinary dysfunction.
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Extractos Vegetales , Canales Catiónicos TRPV , Capsaicina/farmacología , Células HEK293 , Humanos , Extractos Vegetales/farmacología , Serenoa , Canales Catiónicos TRPV/metabolismoRESUMEN
BACKGROUND: Nobiletin exerts beneficial effects on cognitive function in various animal models of Alzheimer's disease. The present study aimed to investigate the benefits and safety of a combination food of nobiletin-rich extract from C. depressa peel for healthy elderly subjects. METHODS: The nobiletin-containing test food (Nobilex®) comprised high-purity nobiletin powder combined with dried root powder of K. parviflora and dried lead powder of P. japonicum and was administered to elderly Japanese subjects once a day for 16 weeks. The Japanese version of the Wechsler Memory Scaled-Revised (WMS-R) was used as a primary evaluation item for the assessment of global memory. Data from a protocol-matched population (Per Protocol Set: PPS) (n = 108) were analyzed. RESULTS: The scores of "general memory" or "visual memory" in the indices of WMS-R were significantly higher in the nobiletin-containing test food group than in the placebo group. The difference in the total WMS-R score was significantly higher in the test-food group (9.0 ± 7.20) than in the placebo group (5.9 ± 7.70). An age-stratified analysis of the WMS-R test showed similar changes in subjects aged â¦74 years to those in the overall subject population. In the stratified analysis involving subjects with an MMSE-J score of between 24 and 28, the "figural memory" subscale score in WMS-R was significantly higher in the test food group than in the placebo group. CONCLUSION: The present results indicate that the nobiletin-containing test food is beneficial for improving memory dysfunction in healthy elderly subjects.
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OBJECTIVES: To examine the effects of vibegron, a selective ß3 -adrenoceptor agonist, used to treat overactive bladder, on muscarinic receptors in the rat bladder, and to predict the occupancy levels of muscarinic receptors by vibegron in the bladders of humans orally administered a clinical dose. METHODS: Muscarinic receptors in the rat bladder and other tissues were examined by a radioligand binding assay using [N-methyl-3 H]scopolamine chloride. The occupancy levels of muscarinic receptors by vibegron in bladders of humans after its oral administration were predicted from the estimation of unbound concentrations in human plasma and urine in the literature. RESULTS: Vibegron (0.1-100 µmol/L) inhibited specific [N-methyl-3 H]scopolamine chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. The 50% inhibitory concentration value of vibegron in the bladder was approximately twofold higher than that in the heart, and approximately 315- and 3.5-fold lower than those in the submaxillary gland and brain, respectively. Therefore, the binding affinity of vibegron for muscarinic receptors was higher in the heart and bladder than in the submaxillary gland and brain. By using the rat bladder receptor binding affinity, occupancy levels of muscarinic receptors in the human bladder were predicted to be 51-91% until 24 h after its oral administration at 50 mg of vibegron. CONCLUSIONS: This is the first study to suggest that vibegron binds to muscarinic receptors in the rat bladder and other tissues, with a potentially higher affinity for the M2 subtype than the M1 and M3 subtypes. These results might be clinically relevant for pharmacotherapy with vibegron for overactive bladder.
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Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Animales , Humanos , Pirimidinonas , Pirrolidinas , Ratas , Receptores Muscarínicos , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
We evaluated the effects of unripe mandarin orange (Citrus unshiu) extract powder (unripe mandarin extract powder [UMEP]) treated with subcritical water on allergic diseases by using animal models. High performance liquid chromatography (HPLC) analysis revealed that subcritical water is a more effective solvent than alcohol and hot water, as it quickly extracted approximately 90% of the functional compounds narirutin (1) and hesperidin (2) from whole fruits. Repeated oral administration of UMEP significantly reversed the peripheral blood flow decline observed during the promotion of allergies after sensitization with the antigen, hen egg-white lysozyme (HEL). UMEP also significantly inhibited compound 48/80-induced scratching behavior in HEL-sensitized mice, which are more sensitive to itching stimuli than are normal mice, without suppressing locomotor activity. In addition, repeated oral administration of UMEP in ovalbumin-challenged guinea pigs significantly suppressed the late phase of nasal airway resistance. This study provides evidence that the subcritical water extract powder of unripe C. unshiu fruit is an effective anti-allergic functional food.
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Antialérgicos , Citrus , Animales , Antialérgicos/farmacología , Cobayas , Ratones , Extractos Vegetales , Polvos , AguaRESUMEN
The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.
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Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Antagonistas Muscarínicos/farmacocinética , Tiazoles/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/farmacocinética , Acetanilidas/administración & dosificación , Acetanilidas/uso terapéutico , Administración Oral , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Animales , Encéfalo/metabolismo , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/uso terapéutico , Contracción Muscular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Glándula Submandibular/metabolismo , Tiazoles/administración & dosificación , Tiazoles/uso terapéutico , Vejiga Urinaria/metabolismo , Agentes Urológicos/administración & dosificación , Agentes Urológicos/uso terapéuticoRESUMEN
Benzodiazepines (BDZs) and non-BDZ sedative-hypnotics are effective for the management of chronic insomnia; however, they are associated with adverse effects such as headache, dizziness, and palpitations. Furthermore, long-term use of these medications is associated with decreased blood pressure (BP) or depressed baroreflex function. Therefore, here, we assessed whether BDZs and non-BDZs cause vasorelaxation directly. Vasorelaxation in response to 22 BDZs, 2 non-BDZs, and tandospirone was determined by myograph methods using isolated Wistar rat thoracic aortas. All the drugs relaxed phenylephrine-contracted rat aortas in a concentration-dependent manner. Zolpidem and tandospirone caused over 80% relaxation at a concentration of 10 µM; diazepam, estazolam, etizolam, and tofisopam caused 60-70% relaxation; whereas 18 other BDZs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, ethyl loflazepate, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, temazepam, and triazolam) and zaleplon caused less than 50% relaxation. The relaxation was partially but significantly inhibited to the same extent by a nitric oxide (NO) synthase antagonist and after endothelium removal. Binding assay of gamma-aminobutyric acid type A receptors was performed using [3H]flunitrazepam. No correlation was observed between vasorelaxation at a concentration of 10 µM and the binding affinities for 23 drugs. The study demonstrated that zaleplon, zolpidem, tandospirone, and many BDZs cause vasorelaxation to different extents via endothelial NO-dependent and endothelium-independent pathways. In conclusion, the direct vasodilatory effects of these drugs may be involved in the mechanisms underlying their adverse effects. Additionally, the decreased BP observed in persons who take BDZs or non-BDZs may be partly due to direct vasodilation.
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Aorta Torácica/efectos de los fármacos , Benzodiazepinas/toxicidad , Hipnóticos y Sedantes/toxicidad , Hipotensión Ortostática/inducido químicamente , Isoindoles/toxicidad , Arterias Mesentéricas/efectos de los fármacos , Piperazinas/toxicidad , Pirimidinas/toxicidad , Vasodilatación/efectos de los fármacos , Animales , Aorta Torácica/fisiopatología , Relación Dosis-Respuesta a Droga , Hipotensión Ortostática/fisiopatología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/fisiopatología , Ratas WistarRESUMEN
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.
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Esclerosis Amiotrófica Lateral/metabolismo , Tronco Encefálico/metabolismo , Extremidad Inferior/inervación , Metales/metabolismo , Mitocondrias/metabolismo , Neuronas Motoras/metabolismo , Células Receptoras Sensoriales/metabolismo , Médula Espinal/metabolismo , Extremidad Superior/inervación , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/terapia , Animales , Tronco Encefálico/patología , Tronco Encefálico/fisiopatología , Progresión de la Enfermedad , Homeostasis , Humanos , Mitocondrias/patología , Neuronas Motoras/patología , Células Receptoras Sensoriales/patología , Médula Espinal/patología , Médula Espinal/fisiopatologíaRESUMEN
We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.
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Compuestos Bicíclicos con Puentes/química , Hexanos/química , Histamina/química , Receptores Histamínicos H3/metabolismo , Histamina/metabolismo , Humanos , Ligandos , Conformación Molecular , Unión Proteica , Receptores Histamínicos H3/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Functional food material, polyamines are considered to be essential for growth factors in virtually all cells. The polyamines putrescine, spermidine and spermine are low molecular weight organic polycations, well known as mediators involved in cell homeostasis. The proposed functions of polyamines are the regulation of ion channels, nucleic acid packaging, signal transduction, cell proliferation, and differentiation, as well as gene expression. In skeletal muscle, regulation of polyamine levels is associated with muscle hypertrophy and atrophy, yet detailed studies are remained to be undergoing. Here, we studied how polyamines may affect the proliferation and/or differentiation of murine myoblast progenitor C2C12 cell line. Upon polyamine treatment of C2C12 cells during induction of myogenic differentiation, the number of myotubes significantly increased. Morphologically, polyamine-treated myotubes exhibited elongated cell body and contained larger amount of nuclei in the cell. On the other hand, the polyamine did not have influence on myoblasts proliferation. Furthermore, compensatory muscle hypertrophy of C57BL6 mice that underwent sciatic nerve transection of the left hindlimb was enhanced by administration of polyamines. Therefore, our study demonstrates that polyamines may play an important role in regulating myogenic differentiation rather than myoblasts proliferation.
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Alimentos Funcionales , Mioblastos , Animales , Homeostasis , Ratones , Ratones Endogámicos C57BL , Músculo EsqueléticoRESUMEN
Diarrhea is often caused by changes in lifestyle, stress, or side effects of drugs. Acanthopanax senticosus root extract (ASRE) has long been used as a functional food remedy with anti-fatigue, neuroprotective, and immunomodulatory activities. However, it is unclear whether ASRE has beneficial effects on gastrointestinal (GI) motility. Therefore, we first investigated whether ASRE directly affects contractile functions of the isolated mouse ileum, and then assessed its effects on GI transit of a charcoal meal in normal mice and a carbachol (CCh)-induced diarrhea mouse model. ASRE caused contraction of the isolated mouse ileum and the maximum contraction was approximately half of that induced by acetylcholine (ACh) administration. In the presence of atropine, this ASRE-induced contraction disappeared, while relaxation responses were observed. However, ASRE reduced potassium chloride- and ACh-induced contractions, and the inhibitory effect was not counteracted by a ß-blocker. Administration of a nitric oxide synthase inhibitor or potassium channel blockers did not affect the ASRE-induced relaxation. Oral administration of ASRE for 1 and 4 d reduced the increased GI transit in CCh-treated but did not affect the GI transit of normal mice. These results indicate that ASRE exhibited dual effects of contraction via muscarinic receptors and direct relaxation on mouse ileal function, and its relaxant effect could be useful in treating diarrhea symptoms, resulting in an increase in the parasympathetic nerve activities.
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Eleutherococcus , Motilidad Gastrointestinal/efectos de los fármacos , Íleon/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Íleon/fisiología , Técnicas In Vitro , Masculino , Ratones Endogámicos ICR , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Raíces de PlantasRESUMEN
In vitro and in vivo binding sites of [3H]-labeled 5-hydroxymethyltolterodine (5-HMT), a new radioligand for labeling muscarinic receptors in rat tissues were characterized. Specific [3H]5-HMT binding in rat tissues was saturable and of high affinity in each tissue. The dissociation constant (Kd) was significantly lower in bladder and heart than in submaxillary gland. Significant levels of in vivo specific [3H]5-HMT binding by intravenous injection of the radioligand were detected in tissues, except for cerebral cortex. Thus, [3H]5-HMT was shown to specifically label muscarinic receptors in rat tissues, suggesting a useful radioligand for labeling muscarinic receptors with high affinity.