ABSTRACT
BACKGROUND: Earlier reports suggest that vitamin D3 (Vit D3) supplementation attenuates Parkinsonism in drug-induced motor deficits. Moreover, the function of Vit D3 may be optimized by co-administration with vitamin A (Vit A). In line with the synergistic interplay between vitamins, we hypothesized that the efficacy of Vit D3 to attenuate Parkinsonism in a haloperidol-induced mouse model of motor deficits would be more potent when concomitantly administered with Vit A. METHODS: Thirty-six (36) adult male mice were randomly divided into six groups of six animals each: the control group, the PD model (haloperidol-treated only group) (-D2), and four other groups treated with haloperidol together with either one or two of the following vitamin supplementations: Vit D3, Vit A, Vit D3 +VA, or bromocriptine a known PD drug respectively. Motor functions were assessed using a battery of neurobehavioral tests in experimental animals, after which brain tissues were harvested and processed for biochemical and histomorphological analysis. RESULTS: We recorded a significant decline in motor activity in the PD mice model treated with haloperidol alone compared to other experimental groups that received vitamin supplementations. The significant decrease in motor activity observed in the PD mice model corresponded with marked neurodegenerative features in the cytoarchitecture of the pyramidal cells in the striatum and primary motor cortex (M1). Furthermore, the haloperidol-induced PD mice model treated with Vit D3 +Vit A showed significant improvement in motor activity and attenuation of oxidative stress levels and neurodegenerative features compared to other groups treated with Vit A, Vit D3 and bromocriptine alone. CONCLUSION: Altogether, our findings suggest that concomitant administration of both Vit D3 and Vit A prevents the development of Parkinsonism features in the haloperidol mouse model of motor deficit. Thus, supplementation with Vit D3 +Vit A may be a viable option for slowing the onset and progression of motor deficits.
Subject(s)
Cholecalciferol , Parkinsonian Disorders , Male , Mice , Animals , Cholecalciferol/pharmacology , Cholecalciferol/therapeutic use , Haloperidol/pharmacology , Bromocriptine , Vitamins/pharmacology , Vitamins/therapeutic use , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Dietary SupplementsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Milk deficiency is a prevalent problem in the world. Daylily (Hemerocallis citrina Borani), called the Chinese mother flower, is a traditional vegetable and is believed to possess a galactagogue effect in China. Flavonoids and phenols are considered as the active ingredients of daylily to promote lactation and improve depression. AIM OF THE STUDY: The aim of this study was to investigate the prolactin effects of freeze-dried powder of flower buds of H. citrina Baroni in rat and its action mechanisms. MATERIALS AND METHODS: The chemical constituents of flower buds of H. citrina Baroni treated by different drying techniques were analyzed by ultrahigh pressure liquid chromatography-mass spectrometry. Sprague-Dawley (SD) rat model induced by bromocriptine was used to evaluate the effect of freeze-dried powder of daylily buds on promoting lactation. Network pharmacology method, ELISA, qPCR, and Western blot were used to clarify the action mechanisms. RESULTS: We detected 657 compounds in daylily buds. The relative contents of total flavonoids and phenols in freeze-dried samples were higher than those in dried ones. Bromocriptine, as a dopamine receptor agonist, can significantly inhibit prolactin in rats. Daylily buds can restore the levels of prolactin, progesterone and estradiol depressed by bromocriptine, effectively improve the milk production of the rat, and promote the repair of rat mammary gland tissue. We analyzed the relationship between the chemical components of daylily buds and the genes related to lactation with network pharmacology method, revealing that flavonoids and phenols may be the active components that promoted milk production via JAK2/STAT5 pathway, which was confirmed by the results of qPCR and Western blot. Daylily buds can increase the mRNA expression of PRLR, CSN2, LALBA and FASN and the protein expression of PRLR, JAK2 and STAT5. CONCLUSION: Daylily buds can improve the insufficient lactation of rats induced by bromocriptine through PRLR/JAK2/STAT5 pathway, and the freeze-dried processing method may better retain the active components of flavonoids and phenols that promote milk in daylily.
Subject(s)
Hemerocallis , Lactation Disorders , Humans , Female , Rats , Animals , Bromocriptine/pharmacology , Hemerocallis/chemistry , Hemerocallis/metabolism , Powders , Prolactin/metabolism , Rats, Sprague-Dawley , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolism , Lactation , Phenols/chemistry , Flavonoids , Janus Kinase 2/metabolismABSTRACT
Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.
Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacology , Molecular Docking Simulation , Receptors, Dopamine/chemistry , Biological Products/analysis , Biological Products/toxicity , Bromocriptine/chemistry , Bromocriptine/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Dopamine Agonists/analysis , Dopamine Agonists/toxicity , Drug Evaluation, Preclinical , Humans , Hydrogen Bonding , Ligands , Molecular Dynamics Simulation , Prolactin/metabolismABSTRACT
BACKGROUND: Prolactin (PRL) is a protein hormone secreted by the anterior pituitary gland that regulates pituitary hormones. Hyperprolactinemia (HPRL), a pathological phenomenon of excessive PRL, can cause infertility in severe cases and is currently treated mainly with Western drugs, such as bromocriptine, a dopamine agonist (DA). Unfortunately, DAs produce psychological side effects which limit their long-term use. Traditional Chinese medicine (TCM) has minimal side effects and good results spanning many years of research. The combined treatment of TCM and Western medicine may enhance treatment efficacy and improve the long-term prognosis in HPRL. To analyze the effects of Bu-shen-zhu-yun decoction (BSZY-D) combined with bromocriptine on serum hormones, anxiety, and pregnancy in hyperprolactinemic infertile patients. METHODS: One hundred patients diagnosed with HPRL infertility from June 2020 to June 2021 in the gynecology clinic of Jiangsu Provincial Hospital of Traditional Chinese Medicine were selected and grouped by envelope method. After excluding patients who withdrew or missed visits, 37 cases assigned to the control group were treated with bromocriptine, and 40 cases assigned to the observation group were treated with bromocriptine combined with BSZY-D. The patients' PRL and kisspeptin (KP) serum indexes, improvements in infertility, Anxiety Self-Assessment Scale (SAS) scores, and improvements in the Insomnia Severity Index Scale (ISI) scores were compared between the two groups. RESULTS: At 3 and 6 months of treatment, serum PRL, SAS, and ISI scores were significantly lower, and serum KP was significantly higher in the observation group than in the control group (P<0.05). During the study period, the pregnancy rates were 62.50% (25/40) and 37.84% (14/37) in the observation and control groups, respectively. The observation group also had significantly fewer early miscarriages [10.00% (4/40) vs. 32.43% (12/37)] and less adverse reactions [7.50% (3/40) vs. 24.32% (9/37)] than the control group (all P<0.05). CONCLUSIONS: The combination of bromocriptine with BSZY-D was superior to bromocriptine alone in treating HPRL and HPRL-related infertility, which also demonstrated a positive effect on patients' sleep and low mood.
Subject(s)
Bromocriptine , Drugs, Chinese Herbal/therapeutic use , Hyperprolactinemia , Infertility, Female , Pregnancy Rate , Anxiety , Bromocriptine/therapeutic use , Female , Humans , Hyperprolactinemia/drug therapy , Kisspeptins/blood , Pregnancy , Prolactin/blood , SleepSubject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin/metabolism , Hypoglycemic Agents/therapeutic use , Acarbose/therapeutic use , Bromocriptine/therapeutic use , Cardiovascular Diseases/blood , Cardiovascular Diseases/prevention & control , Colesevelam Hydrochloride/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/classification , Metformin/therapeutic use , Sulfonylurea Compounds/therapeutic use , Thiazolidinediones/therapeutic use , Treatment OutcomeABSTRACT
Dopamine from tuberoinfundibular dopaminergic (TIDA) neurones tonically inhibits prolactin (PRL) secretion. Lactational hyperprolactinaemia is associated with a reduced activity of TIDA neurones. However, it remains controversial whether the suckling-induced PRL surge is driven by an additional decrease in dopamine release or by stimulation from a PRL-releasing factor. In the present study, we further investigated the role of dopamine in the PRL response to suckling. Non-lactating (N-Lac), lactating 4 hour apart from pups (Lac), Lac with pups return and suckling (Lac+S), and post-lactating (P-Lac) rats were evaluated. PRL levels were elevated in Lac rats and increased linearly within 30 minutes of suckling in Lac+S rats. During the rise in PRL levels, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME) and neurointermediate lobe of the pituitary did not differ between Lac+S and Lac rats. However, dopamine and DOPAC were equally decreased in Lac and Lac+S compared to N-Lac and P-Lac rats. Suckling, in turn, reduced phosphorylation of tyrosine hydroxylase in the ME of Lac+S. Domperidone and bromocriptine were used to block and activate pituitary dopamine D2 receptors, respectively. Domperidone increased PRL secretion in both N-Lac and Lac rats, and suckling elicited a robust surge of PRL over the high basal levels in domperidone-treated Lac+S rats. Conversely, bromocriptine blocked the PRL response to suckling. The findings obtained in the present study provide evidence that dopamine synthesis and release are tonically reduced during lactation, whereas dopamine is still functional with respect to inhibiting PRL secretion. However, there appears to be no further reduction in dopamine release associated with the suckling-induced rise in PRL. Instead, the lower dopaminergic tone during lactation appears to be required to sensitise the pituitary to a suckling-induced PRL-releasing factor.
Subject(s)
Animals, Suckling/physiology , Dopamine/physiology , Hypothalamus/physiology , Lactation/physiology , Prolactin/metabolism , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Bromocriptine/pharmacology , Domperidone/pharmacology , Dopamine/metabolism , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Female , Hypothalamus/drug effects , Median Eminence/drug effects , Median Eminence/metabolism , Pituitary Gland, Intermediate/drug effects , Pituitary Gland, Intermediate/metabolism , Prolactin-Releasing Hormone/metabolism , Rats , Rats, Wistar , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Background: In recent years, nanotechnology with modern advances in the macromolecular design of nano-carriers has proved to be helpful in the development of drugs delivery systems. This research represents a novel co-administration of nano-vehicles, known as liposomes. Liposomes efficiently encapsulate curcumin and bromocriptine (BR) in a polymer structure, which results in enhanced aqueous solubility of the mentioned hydrophobic agents and higher bioavailability of the drugs. Methods: Preparation of curcumin and BR liposomes were carried out by the thin film method, and the amounts of purified drug and its release were analyzed. After dose determination, the human lung cancer cells (QU-DB) were exposed to BR and curcumin liposomes for 12, 24, and 48 h. Then the viability and apoptosis assays were carried out by using tetrazolium dye and flow cytometry technique, respectively. Results: In this research, in vitro anti-cancer effects of former nano-formulations on lung cancer cells was confirmed, and no cytotoxicity effects of these nano-preparations were observed in the normal cells (HFLF-PI5). Discussion: Our findings suggest the nano-liposomal drugs as effective anti-cancer agents; however, additional clinical examinations are required.
Subject(s)
Apoptosis , Bromocriptine/administration & dosage , Bromocriptine/therapeutic use , Curcumin/administration & dosage , Curcumin/therapeutic use , Drug Delivery Systems , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Apoptosis/drug effects , Bromocriptine/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/pharmacology , Drug Liberation , Humans , Liposomes , Lung Neoplasms/pathology , Particle SizeABSTRACT
Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.
Subject(s)
Adipose Tissue, Brown/metabolism , Dopamine/metabolism , Hypothalamus/metabolism , Signal Transduction , Thermogenesis/physiology , Animals , Bromocriptine/administration & dosage , Bromocriptine/pharmacology , Female , Humans , Hypothalamus/drug effects , Injections, Intraventricular , Male , RatsABSTRACT
BACKGROUND: Breast cancer is one of the common causes of mortality for women in Iran and other parts of the world. The substantial increasing rate of breast cancer in both developed and developing countries warns the scientists to provide more preventive steps and therapeutic measures. This study is conducted to investigate the impact of neurotransmitters (e.g., Dopamine) through their receptors and the importance of cancers via damaging immune system. It also evaluates dopamine receptors gene expression in the women with breast cancer at stages II or III and dopamine receptor D2 (DRD2) related agonist and antagonist drug effects on human breast cancer cells, including MCF-7 and SKBR-3. METHODS: The patients were categorized into two groups: 30 native patients who were diagnosed with breast cancer at stages II and III, with the mean age of 44.6 years and they were reported to have the experience of a chronic stress or unpleasant life event. The second group included 30 individuals with the mean age of 39 years as the control group. In order to determine the RNA concentration in all samples, the RNA samples were extracted and cDNA was synthesized. The MCF-7 cells and SKBR-3 cells were treated with dopamine receptors agonists and antagonists. The MTT test was conducted to identify oxidative and reductive enzymes and to specify appropriate dosage at four concentrations of dopamine and Cabergoline on MCF-7 and SKBR-3 cells. Immunofluorescence staining was done by the use of a mixed dye containing acridine orange and ethidiume bromide on account of differentiating between apoptotic and necrotic cells. Flow cytometry assay was an applied method to differentiate necrotic from apoptotic cells. RESULTS: Sixty seven and thirty three percent of the patients were related to stages II and III, respectively. About sixty three percent of the patients expressed ER, while fifty seven percent expressed PR. Thirty seven percent of the patients were identified as HER-2 positive. All types of D2-receptors were expressed in PBMC of patients with breast cancer and healthy individuals. The expression of the whole dopamine receptor subtypes (DRD2-DRD4) was carried out on MCF-7 cell line. The results of RT-PCR confirmed the expression of DRD2 on SKBR-3 cells, whereas the other types of D2- receptors did not have an expression. The remarkable differences in gene expression rates between patients and healthy individuals were revealed in the result of the Real-time PCR analysis. The over expression in DRD2 and DRD4 genes of PBMCs was observed in the patients with breast cancer at stages II and III. The great amount of apoptosis and necrosis occurred after the treatment of MCF-7 cells by Cabergoline from 25 to 100 µmolL-1 concentrations. CONCLUSION: This study revealed the features of dopamine receptors associated with apoptosis induction in breast cancer cells. Moreover, the use of D2-agonist based on dopamine receptors expression in various breast tumoral cells could be promising as a new insight of complementary therapy in breast cancer.
Subject(s)
Breast Neoplasms/genetics , Receptors, Dopamine/genetics , Adult , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Bromocriptine/pharmacology , Cabergoline/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Leukocytes, Mononuclear/metabolism , Middle Aged , Neoplasm Staging , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Remoxipride/pharmacologyABSTRACT
Postpartum dysgalactia is a common clinical problem for lactating women. Seeking out the safe and efficient phytoestrogens will be a promising strategy for postpartum dysgalactia therapy. In this study, the postpartum mice within four groups, including control group, the model group, and the treatment groups intragastrically administrated with normal saline, bromocriptine, bromocriptine plus 17α-ethinyl estradiol, and bromocriptine plus quercetin, respectively, were used. The results showed that quercetin, a kind of natural phytoestrogen, could efficiently promote lactation yield and mammary gland development in the agalactosis mice produced by bromocriptine administration. Mechanically, quercetin, such as 17α-ethinyl estradiol, significantly stimulated prolactin (PRL) production and deposition in the mammary gland in the agalactosis mice determined by western blotting, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Furthermore, quercetin could increase the expression of ß-casein, stearoyl-CoA desaturase, fatty acid synthase, and α-lactalbumin in the breast tissues that are responsible for the production of fatty acid, lactose, and galactose in the milk at the transcriptional level determined by quantitative polymerase chain reaction. Specifically, quercetin promoted primary mammary epithelial cell proliferation and stimulated prolactin receptor (PRLR) expression probably via AKT activation in vitro. In conclusion, this study indicates that estrogen-like quercetin promotes mammary gland development and lactation yield in milk-deficient mice, probably via stimulating PRL expression and release from the pituitary gland, as well as induces PRLR expression in primary mammary epithelial cells.
Subject(s)
Lactation Disorders/drug therapy , Lactation/drug effects , Pituitary Gland/drug effects , Prolactin/biosynthesis , Quercetin/pharmacology , Animals , Bromocriptine , Cells, Cultured , Epithelial Cells/drug effects , Fatty Acids/biosynthesis , Female , Gene Expression/drug effects , Lactose/biosynthesis , Mammary Glands, Animal/drug effects , Mice , Milk , Pituitary Gland/metabolismABSTRACT
Prolactin is a pleiotropic peptide hormone produced by the lactotrophs in the anterior pituitary. Its rate of secretion is primarily regulated by a negative-feedback mechanism where prolactin stimulates the activity of the tuberoinfundibular dopaminergic (TIDA) neurones, increasing their release of dopamine, which accesses the pituitary via the median eminence to suppress further prolactin secretion. In addition to its well established role in lactation, circulating prolactin is secreted in response to stress, although the mechanism by which this is achieved or its cellular targets remains unknown. In the present study, we show that 15 minutes of restraint stress causes an approximately seven-fold increase in circulating prolactin concentration in male mice. Monitoring prolactin receptor activation, using immunohistochemistry to determine the level and distribution of tyrosine phosphorylated signal transducer and activator of transcription 5 (pSTAT5), we show that this stress-induced increase in prolactin interacts with both central and peripheral targets. Restraint stress for 15 minutes significantly increased pSTAT5 staining in the arcuate nucleus, median eminence and the zona fasciculata of the adrenal cortex. In each case, this response was prevented by pretreating the animals with bromocriptine to block prolactin secretion from the pituitary. Interestingly, in contrast to many cells in the arcuate nucleus, stress reduced pSTAT5 staining of the TIDA neurones (identified by dual-labelling for tyrosine hydroxylase). This suggests that there is reduced prolactin signalling in these cells and thus potentially a decline in their inhibitory influence on prolactin secretion. These results provide evidence that prolactin secreted in response to acute stress is sufficient to activate prolactin receptors in selected target tissues known to be involved in the physiological adaptation to stress.
Subject(s)
Adrenal Cortex/metabolism , Hypothalamus/metabolism , Prolactin/physiology , Restraint, Physical , STAT5 Transcription Factor/metabolism , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Bromocriptine/pharmacology , Dopaminergic Neurons/metabolism , Male , Median Eminence/metabolism , Mice , Phosphorylation/physiology , Prolactin/antagonists & inhibitors , Prolactin/blood , Receptors, Prolactin/physiologyABSTRACT
One of the approaches to correct type 2 diabetes mellitus (T2DM) and its complications is the use of drug bromocryptine mesylate (BCM), a selective agonist of type 2 dopamine receptors (DA2R). At the same time, the efficiency and the mechanisms of action of BCM in treatment of severe forms of T2DM are not currently understood. The objective was to study the effect of four-week treatment of male rats with neonatal T2DM model using BCM (300 mg/kg/day) on their metabolic parameters and activity of the adenylyl cyclase signaling system (ACSS) in the hypothalamus. The BCM treatment restored glucose tolerance and its utilization by exogenous insulin, and normalized lipid metabolism by lowering the levels of triglycerides and atherogenic cholesterol increased in T2DM. In the hypothalamus of BCM-treated diabetic rats, the regulation of ACSS by agonists of type 4 melanocortin receptor (MC4R), DA2R and 1B-subtype serotonin receptor, and the expression of Mc4r gene encoding MC4R were restored. Meanwhile, the BCM treatment had no effect on plasma insulin level and insulin production by pancreatic b-cells. The obtained data indicate the significant prospects of BCM to treat severe forms of experimental T2DM, and show that the therapeutic potential of this drug includes its ability to restore the hypothalamic signaling systems sensitive to monoamines and peptide of the melanocortin family, which are responsible for the control of energy metabolism and insulin sensitivity.
Subject(s)
Bromocriptine/pharmacology , Diabetes Mellitus, Experimental , Energy Metabolism/drug effects , Hypothalamus , Signal Transduction/drug effects , Adenylyl Cyclases/metabolism , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Hypothalamus/metabolism , Hypothalamus/pathology , Insulin/metabolism , Male , Rats , Receptor, Melanocortin, Type 4/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , Receptors, Dopamine D2/metabolismABSTRACT
The diversity and uniqueness of flatworm G protein coupled receptors (GPCRs) provides impetus for identifying ligands useful as tools for studying flatworm biology, or as therapeutics for treating diseases caused by parasitic flatworm infections. To catalyse this discovery process, technologies optimized for mammalian GPCR high throughput screening need be transposed for screening flatworm GPCRs. Here, we demonstrate the utility of a genetically encoded cAMP biosensor for resolving the properties of an abundantly expressed planarian serotonergic GPCR (S7.1R). Application of this methodology resolved the real time kinetics of GPCR modulation by ligands and demonstrated a marked difference in the kinetic action of antagonists at S7.1R. Notably, bromocriptine caused a protracted inhibition of S7.1R activity in vitro and a protracted paralysis of planarian movement, replicating the effect of S7.1R in vivo RNAi. The lengthy inhibition of function caused by bromocriptine at this abundantly expressed GPCR provides a useful tool to ablate serotonergic signaling in vivo, and is a noteworthy feature for exploitation as an anthelmintic vulnerability.
Subject(s)
Anthelmintics/pharmacology , Bromocriptine/pharmacology , Planarians/drug effects , Planarians/enzymology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Serotonergic Neurons/drug effects , Serotonin Antagonists/pharmacology , Animals , Drug Evaluation, Preclinical/methods , Kinetics , Locomotion/drug effectsABSTRACT
Previously, we demonstrated that maternal prolactin inhibition at the end of lactation, using bromocriptine (BRO), leads to an increase in leptin transfer via milk and induces the adult progeny to present hypothyroidism, leptin resistance and metabolic syndrome (obesity, hyperglycemia, hypertriglyceridemia, lower HDL). To test if these alterations are due to direct BRO action on the pups, in the present study we evaluated the long-term effects of direct injection of BRO (0.1µg/once daily) in male Wistar rats from postnatal (PN) day 1 to 10 (early treatment) or from PN11 to 20 (late treatment) on: food intake, body mass, cardiovascular parameters, hormone profile, hypothalamic leptin signaling, glucose homeostasis and thyroid hormone-dependent proteins. The respective controls were injected with methanol-saline. Offspring were killed at adulthood (PN180). Adult PN1-10 BRO-treated animals had lower food intake, hypoprolactinemia, lower leptin action (lower OBR-b, STAT-3 and SOCS-3 mRNA levels in the arcuate nucleus), lower TRH-TSH-thyroid axis as well as lower thyroid hormone markers. On the other hand, adult animals that were BRO-treated during the PN11-20 period showed hyperphagia, higher blood pressure, higher prolactinemia and OBR-b, higher TRH and plasma T3, hypercorticosteronemia as well as higher Dio2 and UCP1 mRNA expression in the brown adipose tissue. Glucose homeostasis was not changed treatment in either period. Our data show that early and late dopamine overexposure during lactation induces diverse metabolic disturbances later in life, increasing the risk of thyroid dysfunction and, consequently, changes in prolactinemia.
Subject(s)
Bromocriptine/pharmacology , Prolactin/blood , Thyroid Gland/drug effects , Thyroid Hormones/blood , Animals , Animals, Newborn , Blood Pressure/drug effects , Body Weight/drug effects , Eating/drug effects , Heart Rate/drug effects , Hypothalamus/drug effects , Hypothalamus/metabolism , Leptin/metabolism , Male , Rats , Rats, Wistar , Thyroid Gland/metabolismABSTRACT
Cardiometabolic disorder (CMD) is a cluster of diseases, including cardiovascular diseases (CVDs), metabolic syndrome (MS) and diabetes mellitus (DM). Cardiometabolic disorders (CMDs) remain the principal cause of death in both developed and developing countries, accounting for nearly 32% of all deaths worldwide per year. In addition, dyslipidemia, angina, arrhythmia, cardiac failure, myocardial infarction (MI), and diabetes mellitus represent the leading killer with an estimated 19 million people died from CMDs in 2012. By 2030 more than 23 million people will die annually from CVDs. Existing drugs are not efficient enough to reduce the disease burden as well as mortality. Therefore, there is an urgent demand for new drugs in this area to reduce the mortality and control the associated disability. Nonetheless, new drug discovery (NDD) in CMDs has become more challenging for last couple of decades due to increased expenses and decreased success rate. In such a scenario, drug repositioning in the CMDs appears promising for introducing existing drugs for new therapeutic indication. Repositioning is quite an old strategy dating back to 1960s and mainly followed by serendipitous observations during clinical use of drugs. A major advantage of repositioning is that the safety profile of the drug is well established thus reducing the chances of failure due to adverse toxic effects. In addition, repositioning requires less time and investment than NDD. Considering these facts, pharmaceutical companies are now becoming increasingly interested in drug repositioning. In this follow-up, we have talked about the concept of repositioning with important examples of repositioned drugs in cardiometabolic disorder.
Subject(s)
Cardiovascular Diseases/drug therapy , Drug Evaluation, Preclinical/methods , Drug Repositioning/methods , Metabolic Syndrome/drug therapy , Allopurinol/pharmacology , Aspirin/pharmacology , Bromocriptine/pharmacology , Clonidine/pharmacology , Colesevelam Hydrochloride/pharmacology , Diabetes Mellitus/drug therapy , Drug Discovery , Humans , Piperazines/pharmacology , Tadalafil/pharmacologyABSTRACT
Catatonia is associated with psychomotor symptoms and severe disturbances of executive functioning. While the prognosis is good in most cases, malignant catatonia still continues to occur. The first-line choice for drug therapy is lorazepam, which usually results in a good response. In catatonic stupor, i.e. immobility and stupor, the first-line therapy is electrotherapy, preferably at an earliest possible stage. In mania, catatonia may become manifest also as psychomotor excitement. Electrotherapy can be used primarily in malignant catatonia, with dantrolene and bromocriptin also finding use in a critical situation.
Subject(s)
Catatonia/therapy , Anticonvulsants/therapeutic use , Antiparkinson Agents/therapeutic use , Bromocriptine/therapeutic use , Dantrolene/therapeutic use , Electroconvulsive Therapy , Humans , Lorazepam/therapeutic use , Muscle Relaxants, Central/therapeutic use , PrognosisABSTRACT
Yiru Tiaojing Granule, a traditional Chinese medicine formula, is used to treat hyperprolactinemia. This study was conducted to evaluate the mechanism of action and pharmacological activity of Yiru Tiaojing Granule on prolactin secretion. The animal model of hyperprolactinemia was induced by metoclopramide. The dopamine D2 receptor in hyperprolactinemia rat models was analyzed by immunohistochemistry. The biochemical parameters, including a follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, and prolactin, were measured by an enzyme-linked immunosorbent assay. Furthermore, the expression of prolactin and the dopamine D2 receptor was analyzed by Western blotting. The components in the Yiru Tiaojing Granule-medicated serum were assayed by liquid chromatography-tandem mass spectrometry. The Yiru Tiaojing Granule significantly decreased the prolactin level in the hyperprolactinemia rat model, and increased the estradiol, luteinizing hormone, and progesterone levels. The high and medium doses of Yiru Tiaojing Granule reduced dopamine D2 receptor expression in the brain (p < 0.001) and produced a similar effect on bromocriptine (p < 0.001). Yiru Tiaojing Granule-medicated serum reduced (p < 0.001) prolactin expression in MMQ cells in a concentration-dependent manner, but had no effects on GH3 cells. The level of the dopamine D2 receptor in MMQ cells was also increased dose-dependently (p < 0.05). In addition, the protein kinase A and cyclic adenosine monophosphate in MMQ cells were significantly attenuated dose-dependently by treatment with a high and medium dose of Yiru Tiaojing Granule-medicated serum (p < 0.05) and bromocriptine-medicated serum (p < 0.01). The results suggested that Yiru Tiaojing Granule was effective against hyperprolactinemia, and the activation of the dopamine D2 receptor, which was related to the second messenger cyclic adenosine monophosphate and protein kinase A, might be the potential mechanism.
Subject(s)
Drugs, Chinese Herbal/pharmacology , Hyperprolactinemia/drug therapy , Animals , Brain/drug effects , Brain/metabolism , Bromocriptine/pharmacology , Cell Line/drug effects , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/administration & dosage , Female , Haloperidol/pharmacology , Hyperprolactinemia/metabolism , Medicine, Chinese Traditional/methods , Progesterone/blood , Prolactin/blood , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolismABSTRACT
At birth, a male child presented a 6 cm tumour in the right leg. The tumour was partially removed after just 12 days. Histology showed a congenital fibrosarcoma associated with reactive lymphadenitis. A first cycle of adjuvant chemotherapy did not prevent the rapid progression of the disease. Subsequent evaluation for surgical removal raised serious concerns due to the need for a major operation involving total amputation of the right leg and hemipelvectomy. Since surgery could not exclude the possibility of disease recurrence and since the traditional cycles of chemotherapy did not offer any possibility of a cure, the parents opted for the Di Bella Method. The combined use of Somatostatin, Melatonin, Retinoids solubilized in Vit. E, Vit. C, Vit. D3, Calcium, and Chondroitin sulfate associated with low doses of Cyclophosphamide resulted in a complete objective response, still present 14 years later, with no toxicity and without the need for hospitalization, allowing a normal quality of life and perfectly normal adolescent psycho-physical development.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fibrosarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Ascorbic Acid/administration & dosage , Bromocriptine/administration & dosage , Calcium/administration & dosage , Cholecalciferol/administration & dosage , Chondroitin Sulfates/administration & dosage , Cyclophosphamide/administration & dosage , Fibrosarcoma/congenital , Humans , Infant, Newborn , Leg , Maintenance Chemotherapy , Male , Melatonin/administration & dosage , Remission Induction , Retinoids/administration & dosage , Soft Tissue Neoplasms/congenital , Somatostatin/administration & dosage , Vitamin E/administration & dosage , Vitamins/administration & dosageABSTRACT
BACKGROUND: Antipsychotic drugs frequently cause amenorrhoea and galactorrhoea. Jasmine flowers used topically were as effective as oral Bromocriptine in suppressing puerperal lactation. This study aims to evaluate the efficacy and safety of intranasal jasmine flower extract (JFE) to reduce prolactin levels of patients on stable doses of antipsychotic drugs. METHOD: This is a randomized, double blind, crossover clinical trial. An aqueous-ethanol extract of jasmine flowers was prepared and used as nasal drops. A decrease in serum prolactin of ≥25 ng/mL was considered a significant response. RESULTS: Ten out of 35 women had a significant drop in the serum prolactin while on the JFE. The non-responders to JFE were on higher doses of antipsychotic drugs. The main side effect was a transient and mild burning sensation in the nose. A cost analysis favoured JFE over dopamine agonists. CONCLUSION: JFE contains a prolactin-lowering substance which needs further characterisation.
Subject(s)
Hyperprolactinemia/drug therapy , Jasminum , Phytotherapy , Plant Extracts/administration & dosage , Adolescent , Adult , Antipsychotic Agents/adverse effects , Bromocriptine/adverse effects , Cross-Over Studies , Double-Blind Method , Female , Flowers , Humans , Hyperprolactinemia/blood , Hyperprolactinemia/chemically induced , Middle Aged , Postpartum Period , Prolactin/blood , Treatment OutcomeABSTRACT
Breastfeeding is associated with obesity prevention. We showed previously that prolactin inhibition at the end of lactation causes hyperleptinemia at weaning (PN21) and programs for obesity, insulin resistance, dyslipidemia, and leptin resistance (PN180). Here, we evaluate the source of neonatal hyperleptinemia and how it develops during the nutritional transition from milk through solid food. Lactating rats were treated with bromocriptine (BRO), a prolactin inhibitor, 0.5 mg twice a day, or saline (CON) for the last 3 days of lactation. All parameters were studied at PN22 and PN30. At PN22, BRO-treated rats showed lower food intake, body mass, and body length. At PN30, only body length and mesenteric fat mass were lower. Despite normal plasma leptin levels at PN22, the adipose tissue leptin mRNA expression was lower, while plasma leptin was higher in PN30, possibly due to a higher adipose mesenteric tissue production. At PN22, the hypothalamus seems to be more sensitive to leptin, since OBR and STAT3 are higher. Conversely, at PN30 leptin signaling pathway is suggestive of leptin resistance with lower STAT3 and higher SOCS3 in hypothalamus and consequently higher NPY. Glycemia was lower at PN22 and higher at PN30, without changes in plasma insulin levels. At PN30, BRO-treated rats had other metabolic changes such as higher plasma cholesterol, lower HDL-c, higher hepatic cholesterol and AST, suggesting a liver dysfunction. Our data show that milk supply can exert a crucial role in the imprinting of a second leptin peak, which is important for survival adaptation to adverse nutritional conditions.