Search

[Display omitted] Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies. [ABSTRACT FROM AUTHOR]

Peripartum cardiomyopathy (PPCM) is a rare disorder in which left ventricular systolic dysfunction and heart failure symptoms occur during the peripartum period. Inhibition of prolactin secretion by bromocriptine mediates beneficial effects on cardiac function in PPCM. Mental disorders are also associated with the onset of PPCM. Psychiatric medications for mental disorders would affect serotonin production and tryptophan and dopamine metabolism, and they are associated with PPCM. Conversely, bromocriptine affects psychiatric symptoms; therefore, the treatment of PPCM complicated by mental disorders using bromocriptine may be difficult. Herein, we report cases of two patients with PPCM and mental disorders successfully treated with bromocriptine therapy. The first case involved a 33-year-old woman with a history of atypical depression and anxiety disorder, who developed PPCM with a left ventricular ejection fraction (LVEF) of 19 %. The second case was that of a 42-year-old woman with a history of bipolar and panic disorders who developed PPCM with an LVEF of 18 %. Both patients were administered bromocriptine; however, psychiatric symptoms did not worsen and cardiac function improved. We also review the literature on the relationship between PPCM and mental disorders. Mental disorders and psychiatric medications may be associated with the onset of peripartum cardiomyopathy (PPCM). Although bromocriptine has beneficial effects on PPCM, it has also been reported to increase the risk of worsening psychiatric symptoms; therefore, the efficacy and safety of bromocriptine in PPCM patients with mental disorders is controversial. Our cases showed that bromocriptine can be used safely without worsening psychiatric symptoms in PPCM with mental disorders. [ABSTRACT FROM AUTHOR]

Bromocriptine (BRM), a dopamine 2 receptor agonist, is a common drug for inducing estrus in dogs. It is also used for the treatment of some endocrine abnormalities and has some cardiovascular consequences in the patients under treatment. The current study aimed to evaluate its effects on the cardiovascular function of dogs during administration and the subsequent induced estrus cycle. Eight non-pregnant female dogs were assigned into control and treatment groups. The control group (n = 3) were dogs that showed proestrus naturally. The treatment group (n = 5) received oral incremental (μg/kg) doses (100 on days 1 and 2, 200 on days 3, 4, and 400 on days 5 until the proestrus expression) of BRM tablets (2.5 mg; Iran-Hormone Co, Iran). The left ventricle function, carotid blood flow indices, and systolic (SAP) and diastolic (DAP) arterial pressure were recorded every two days. The phases of the cycle were determined using a vaginal smear. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI) had a sharp decline following the administration of BRM (P < 0.05). The carotid PSA, EDV, RI, and pulse index were lower during induced estrus compared to the control (p < 0.05). BRM-induced estrus showed a different pattern of changes compared to the normal cycle from day 9 (p < 0.05) onwards. The cardiovascular effects of BRM remained for days after the termination of administration which may interfere with reproductive functions. • The quick effects of Bromocriptine administration are a sharp decline in carotid hemodynamics, e.g. RI, PSV, EDV. • The carotid hemodynamic parameters are different in bromocriptine-induced estrus compared to normal. • Cardiac parameters, e.g., FS, SAP, and DAP did not show a similar in induced and normal estrus. [ABSTRACT FROM AUTHOR]

[Display omitted] Intestinal drug solubility is a key parameter controlling oral absorption but varies both intra and inter individuals and between the fasted and fed states, with food intake known to alter the bioavailability of many compounds. Intestinal solubility can be measured in vitro either using sampled fed human intestinal fluid (FeHIF) or simulated fed intestinal fluid (SIF) but neither approach is optimal. FeHIF is difficult to obtain and variable, whilst for fed SIF multiple recipes are available with no consensus on the ideal version. A recent study characterised FeHIF aspirates using a multidimensional approach and calculated nine simulated media recipes that covered over ninety percent of FeHIF compositional variability. In this study the equilibrium solubility of thirteen drugs have been measured using the nine simulated media recipes and compared to multiple previous design of experiment (DoE) studies, which have examined the impact of fed SIF media components on solubility. The measured nine media solubility data set is only statistically equivalent to the large scale 92 media DoE in 4 out of 13 drug comparisons, but has improved equivalence against small scale DoEs (9 or 10 media) with 6 out of 9 or 10 out of 12 (9 and 10 media respectively) equivalent. Selective removal of non-biorelevant compositions from the 92 media DoE improves statistical equivalence to 9 out of 13 comparisons. The results indicate that solubility equivalence is linked to media component concentrations and compositions, the nine media system is measuring a similar solubility space to previous systems, with a narrower solubility range than the 92 point DoE but equivalent to smaller DoE systems. Phenytoin and tadalafil display a narrow solubility range, a behaviour consistent with previous studies in fed and fasted states and only revealed through the multiple media approach. Custom DoE analysis of the nine media results to determine the most statistically significant component influencing solubility does not detect significant components. Indicating that the approach has a low statistical resolution and is not appropriate if determination of media component significance is required. This study demonstrates that it is possible to assess the fed intestinal equilibrium solubility envelope using the nine media recipes obtained from a multi-dimensional analysis of fed HIF. The derivation of the nine media compositions coupled with the results in this study indicate that the solubility results are more likely to reflect the fed intestinal solubility envelope than previous DoE studies and highlight that the system is worthy of further investigation. [ABSTRACT FROM AUTHOR]

Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period. • 72 h sleep recordings after bromocriptine treatments during estrus cycle and postpartum period. • Sleep changes showed strong dependency on the estrus cycle phase of the drug application. • Stronger sleep effects in the dark during estrus cycle but in light during postpartum. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated nonsteroidal antiinflammatory drug treatment in early lactation had a positive impact on whole-lactation milk production in older cows. The objective of this study was to evaluate proliferative, transcriptional, and epigenetic changes in the mammary gland that could explain increased production responses due to nonsteroidal antiinflammatory drug treatment. Sodium salicylate (SAL; 125 g/d) or water (CON) were administered via oral drench to multiparous Holstein cows (n = 8/treatment) once daily for 3 d beginning approximately 24 h after parturition, and mammary tissue was collected on d 1, 4, and 45 postpartum. Day 1 tissue was collected immediately preceding the initial drench, and d 4 tissue was collected 24 h following the final drench. Blood was collected twice weekly and analyzed for plasma glucose, insulin, β-hydroxybutyrate, free fatty acids, and prolactin. Cows were milked twice daily until d 7 of lactation, and thrice daily for the remainder of the study. Total RNA extracted from tissue was deep-sequenced and analyzed for differential gene expression using DESeq2. We detected no treatment effect on milk yield or plasma metabolites through 45 d of lactation; additionally, no change in mammary epithelial cell proliferation was detected when assessed by Ki67 labeling. Comparison of SAL versus CON revealed that only 16 of 18,286 genes were differentially expressed (false discovery rate <0.1) in mammary tissue collected on d 45, whereas no differentially expressed genes due to treatment were detected on d 1 or 4. Analysis of transcriptional differences over time showed downregulation of pathways related to immune cell recruitment and differentiation, and extensive overlap with pathways related to cholesterol synthesis and liver X receptor signaling. Global DNA methylation of mammary tissue was decreased for CON compared with SAL. Transcriptome analysis emphasized extensive involvement of immune-related signaling pathways in the switch from lactogenesis to galactopoiesis, and changes in methylation with SAL treatment merit future investigation into epigenetic effects on milk production. [ABSTRACT FROM AUTHOR]

Canine (Canis familiaris) pseudocyesis, pseudopregnancy, false pregnancy or nervous lactation is a frequent syndrome observed in non-pregnant, late diestrous or early anestrous females that is characterized by different degrees of mammary gland enlargement, maternal behavior and lactation. Further education about this frequent canine physiological event is still necessary to ensure optimal diagnosis and treatment strategies. Thus, the aim of this article was to review and update the physiopathology, physical and behavioral signs, diagnosis, treatment and prevention of pseudocyesis in bitches in which it is a clinical problem. • Canine pseudocyesis (PSC) is a frequent syndrome observed in late diestrous females. • PSC is characterized by mammary gland enlargement, maternal behavior and lactation. • Further education is still necessary to ensure optimal diagnosis and therapeutics. • Since the last review was published substantial research has been carried out on PSC. • PSC physiopathology, signs, treatment and prevention were reviewed and updated. [ABSTRACT FROM AUTHOR]

Objective: Vaginal bromocriptine significantly reduces heavy menstrual bleeding and pain in women with diffuse adenomyosis. The aim of this pilot study was to evaluate whether imaging findings of adenomyosis, as assessed by transvaginal ultrasound (TVU) and magnetic resonance imaging (MRI) reflect changes induced by the bromocriptine treatment.Study Design: Eighteen women, aged 35-50, with heavy menstrual bleeding reporting Pictorial Blood Loss Assessment Chart (PBLAC) scores >100 and diffuse adenomyosis according to both MRI and TVU were included. The subjects underwent treatment with vaginal bromocriptine for 6 months. MRI and TVU were performed at baseline and after 6 months of medication.Results: Mean age of the participants was 44.8 years, 77.8 % reported PBLAC scores > 250 and 66.7 % reported moderate to severe pain during menstruation at baseline. As compared to baseline, TVU revealed a thinner maximal Junctional Zone (JZmax) (8.5 mm [5.2-14] vs 7.9 mm [5-11.2], p = 0.02) at 6 months. Asymmetric wall thickening was seen in 13 (72 %) at baseline, and in 6 (33 %) women at 6 months, p = 0.02. No significant changes were seen in irregular endometrial-myometrial border, presence of fan-shaped shadowing, cystic changes, striations, hyperechogenic islands or lesion extension. MRI showed no significant difference in JZmax (16.0 mm[12.1-27.7] vs 15.5 mm [9.5-25.8], p = 0.81), JZdifference (9.5 mm[4.8-21.6] vs 8.4[3.8-19.5], p = 1) or Ratio JZ/myometrium (0.6 [0.5-0.8] vs. 0.6[0.4-0.8], p = 0.9) at baseline vs 6 month. Cystic lesions in the JZ were found in 9 women (50 %) before, and in 5 women (28 %) at 6 months, p = 0.13.Conclusion: TVU showed a significant decrease in JZ max and a reduced number of women with asymmetric myometrial wall thickness. The changes seen in this small pilot study may indicate that vaginal bromocriptine have an impact on adenomyosis that is reflected in radiological appearance. [ABSTRACT FROM AUTHOR]

The biogenic amine dopamine (DA) regulates various physiological and behavioral processes in insects through binding with specific receptors. Three types of typical receptors are known to date. Previously, we achieved functional and pharmacological characterization of the three DA receptors in the silkworm Bombyx mori (BmDopR1–3). BmDopR1 and BmDopR2 are functionally classified as D1-like DA receptors, and BmDopR3 as D2-like. The present pharmacological data and our previous studies suggested that bromocriptine (Bro), which acts as an agonist on the DA D2 receptors and also interacts with various serotonin and adrenergic receptors in vertebrates, is an agonist that also acts specifically on BmDopR3, with little effect on BmDopR1 and BmDopR2 in silkworms. Exploiting this subtype specificity of Bro, to offer clues on the involvement of DA and its receptors in silkworm feeding behavior, Bro was injected into fifth instar larvae and subsequent feeding and related behaviors (feeding amount, excretion amount, mandibular movement, and feeding behavior observation) were quantitatively evaluated. Bro injection increased feeding and excretion amounts but did not affect mandibular chewing speed. Visual observation of feeding behavior for 1 h revealed the prolongation of feeding and related moving time in Bro-injected larvae. Collectively, these results suggest that Bro directly acted on BmDopR3 as an agonist and promoted feeding and related behaviors in silkworm larvae. [Display omitted] • Bromocriptine acts specifically on a silkworm D2-like dopamine receptor BmDopR3 to reduce intracellular cAMP levels. • Bromocriptine injection promotes feeding and excretion of silkworms and affects no mandibular chewing speed. • Visual observation reveals the prolongation of feeding and related moving time in bromocriptine-injected larvae. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Hypos in the methodologies have been corrected • Limitations of the behavioral test was added in the discussion section as suggested by reviewer 1 and 2 • The abbreviations of the groups and legends in Figs. 4–6 have been revised and made consistent with other figures. [ABSTRACT FROM AUTHOR]

Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80–90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40–50% of treated lactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required. [ABSTRACT FROM AUTHOR]

The relationship between prolactinoma and obesity has not been well explained yet. This report introduced the diagnosis and treatment course of a severely obese male patient. After a series of examinations, the patient was finally diagnosed as prolactinoma after excluding other endocrine-related diseases, like diabetes. His plasma prolactin level (PRL) dropped after treatment with bromocriptine, and so did his weight. It is indicated that prolactinoma may lead to the occurrence of obesity, especially in male patients. The abnormal insulin metabolism caused by the elevation of PRL may be the main reason for this phenomenon. The case provides a fresh idea to control the weight of obese teenagers. [ABSTRACT FROM AUTHOR]

First-line treatment for prolactin-producing pituitary adenomas is dopamine agonist (DA) therapy. This is the first study to analyze the rate of radiographic and hormonal regression of prolactinomas in response to DA therapy to better understand what time frame we consider DA treatment failure. We searched the electronic medical records of 3 tertiary care medical institutions for patients with prolactinomas. The primary outcome was tumor volume and prolactin (PRL) levels at various time points. The secondary outcome was indicators of treatment failure. Modeling by both linear and exponential models was tested to determine potential predictors of response magnitude and treatment failure by multivariate and regression analyses respectively. There were 99 patients (53% male) included in this analysis. The mean patient age was 42.7 years ± 14.5, and mean width/volume of tumor at diagnosis was 12.3 mm and 1.3 cm3, respectively. The mean PRL level at diagnosis was 593.2 ng/mL (79–7913). Modeling indicated a plateau at 68.2% initial volume (95% confidence interval 61.7–73.5) by 12.6 months and a PRL plateau of 21.4 ng/mL (95% confidence interval 0–92.5) by 3.3 months. Multivariate analyses revealed male sex (odds ratio 0.168; P = 0.036) to be a predictor of faster PRL response to DA therapy. Prolactinomas plateau in PRL levels and the rate of size regression within the first year of DA treatment. Prolactinomas with lack of size regression and failure to reach normalization of PRL levels by 12 months may be considered for other management strategies. [ABSTRACT FROM AUTHOR]

Highlights • Expression of RIP3 and pMLKL could be induced by bromocriptine in human prolactinoma. • Bromocriptine induced necroptosis of prolactinoma cells, with ultrastructural changes characterized by ruptured membrane, the lysed cytoplasm, and especially the dramatically swollen mitochondria. • Bromocriptine induced RIP3/MLKL-dependent necroptosis of prolactinoma cells through PGAM5-CypD pathway. Abstract Bromocriptine, the most commonly used dopamine (DA) receptor agonists for prolactinoma, can effectively reduce tumor size of prolactinoma, but the mechanism was not fully understood. Apoptosis had been well-recognized to contribute to the tumor mass regression caused by bromocriptine. However, whether other types of non-apoptotic cell death involved in the bromocriptine-induced prolactinoma shrinkage had not been fully clarified. The newly discovered molecular mechanism of necroptosis provides the possibility to examine this programmed necrosis in the pharmacological function of bromocriptine. The aim of present study was to evaluate and investigate the underlying mechanism of necroptosis in involution of prolactinoma induced by bromocriptine. By immunohistochemistry, we found that the numbers of receptor-interacting serine-threonine kinase 3(RIP3) and phosphorylated mixed lineage kinase domain-like protein (pMLKL)-positive cells and their expression intensities were increased in patients with prolactinoma after bromocriptine therapy. For further exploring the mechanism of bromocriptine, prolactinoma cell line (MMQ cells) was adopted to study the mechanism of necroptosis in vitro. Cell viability and ATP level of MMQ cells were decreased, while reactive oxygen species (ROS) level was increased after bromocriptine treatment. The above effects could be partially reversed by Necrostatin-1, an inhibitor of necroptosis. Ultrastructural study further confirmed the necroptosis of MMQ cells, which was characterized by ruptured membrane, dissolved cytoplasm and especially the dramatically swollen mitochondria. Furthermore, we demonstrated that bromocriptine induced RIP3/MLKL-dependent necroptosis of prolactinoma cells and phosphoglycerate mutase family 5(PGAM5)/ Cyclophilin D (CypD) pathway was involved. The results suggested that necroptosis might be a promising target for clinical therapy for prolactinoma. [ABSTRACT FROM AUTHOR]

Highlights • PDA coating was deposited on hydrated TCS via a simple dip-coating approach. • Ca(OH) 2 resulted in a faster deposition of PDA coating on hydrated TCS substrate. • ACP precipitated rapidly on the surface of PDA-coated TCS within 5 min in SBF. Abstract A layer of polydopamine (PDA) was successfully deposited on hydrated tricalcium silicate (TCS) substrate via facile dip-coating of hydrated TCS disk in an aqueous solution of dopamine. The results showed that the continuous release of Ca(OH) 2 from hydrated TCS substrate accelerated reaction of noncovalent self-assembly and covalent polymerization of dopamine and therefore a faster deposition of PDA coating on hydrated TCS substrate. Furthermore, amorphous calcium phosphate (ACP) that is the precursor phase of bone-like hydroxyapatite (HA) can rapidly precipitate on the surface of PDA-coated TCS within 5 min in simulated body fluid (SBF). [ABSTRACT FROM AUTHOR]

Peripartum cardiomyopathy is a life-threatening condition that requires urgent diagnosis and management. Bromocriptine was established as disease specific therapy; less data is known about Cabergolin which is another prolactin secretion inhibitor. In this paper we report 4 peripartum cardiomyopathy cases treated successfully with Cabergoline, including a cardiogenic shock case requiring mechanical circulatory support. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [Display omitted] • Flavonoids and phenols in FHCP may be the active ingredients. • FHCP has ability of improvement of lactation. • FHCP can activate JAK2-STAT5 pathways. [ABSTRACT FROM AUTHOR]

Compared with levodopa, dopamine agonists (DAs) as initial treatment are associated with lower incidences of motor complications in early Parkinson's disease (PD). There is no strong evidence that a given DA is more potent in lower incidences of motor complications than another. We performed a network meta-analysis of levodopa versus DAs as monotherapy in early PD to access the risk of motor complications. Databases were searched up to June 2022 for eligible RCTs. Levodopa and four DAs (pramipexole, ropinirole, bromocriptine and pergolide) were investigated. The incidences of motor complications and efficacy, tolerability and safety outcomes were analyzed. Nine RCTs (2112 patients) were included in the current study. The surface under the cumulative ranking curve (SUCRA) indicated that levodopa ranked first in the incidence of dyskinesia (0.988), followed by pergolide, pramipexole, ropinirole, and bromocriptine (0.704, 0.408, 0.240, 0.160). Pramipexole was least prone to wearing-off (0.109) and on-off fluctuation (0.041). Levodopa performed best in improvements of UPDRS-II, UPDRS-III, and UPDRS-II + III (0.925, 0.952, 0.934). Bromocriptine ranked first in total withdrawals and withdrawals due to adverse events (0.736, 0.751). Four DAs showed different adverse events profiles. In the two non-ergot DAs, ropinirole is associated with a lower risk of dyskinesia while pramipexole is associated with lower risks of wearing-off and on-off fluctuations. Our research may facilitate head-to-head research, larger sample sizes, long following-up time RCTs to confirm the findings of this network meta-analysis. [ABSTRACT FROM AUTHOR]

Abstract CLBQ14 is an 8-hydroxyquinoline analogue that inhibits methionine aminopeptidase (MetAP), an enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP has been validated as druggable target for some infectious diseases, and its inhibitors have been investigated as potential therapeutic agents. In this study, we developed and validated a liquid chromatography tandem-mass spectrometry (LC-MS/MS) method for the quantification of CLBQ14 in solution, and in rat plasma and urine. This method was applied to the pharmacokinetic evaluation of CLBQ14 in adult male Sprague Dawley (SD) rats. Chromatographic separation was achieved using an ultra-high-performance liquid chromatography (UHPLC) system equipped with Waters XTerra MS C 18 column (3.5 μm, 125 Å, 2.1 × 50 mm) using 0.1% formic acid in acetonitrile/water gradient system as mobile phase. Chromatographic analysis was performed with a 4000 QTRAP® mass spectrometer using MRM in positive mode for CLBQ14 transition [M + H]+ m/z 257.919 → m/z 151.005, and IS (clioquinol) transition [M + H]+ m/z 305.783 → m/z 178.917. CLBQ14 was extracted from plasma and urine samples by protein precipitation. The retention times for CLBQ14 and IS were 1.31 and 1.40 min respectively. The standard curves were linear for CLBQ14 concentration ranging from 1 to 1000 ng/mL. The intra-day and inter-day accuracy and precision were found to be within 15% of the nominal concentration. Extraction recoveries were >96.3% and 96.6% from rat plasma and urine respectively, and there was no significant matrix effect from the biological matrices. CLBQ14 is stable in samples subjected to expected storage, preparation, and handling conditions. Pharmacokinetic studies revealed that CLBQ14 has a bi-exponential disposition in SD rats, is extensively distributed with a long plasma half-life and is eliminated primarily by liver metabolism. [ABSTRACT FROM AUTHOR]

Background Prolactinomas are the most common functional pituitary adenomas and dopamine agonists are the primary therapy. However, some patients are resistant to dopamine agonists. Recently, metformin has been proposed as a cancer treatment. Case Description This study is a retrospective review of 2 cases including 1 patient with prolactinoma who was resistant to bromocriptine, diagnosed with impaired glucose tolerance, and administered metformin. Surprisingly, combining the patient's treatment with metformin decreased prolactin (PRL) levels to 12 ng/mL and significantly decreased the size of the tumor after 1 year of combination therapy. As menstruation resumed and galactorrhea resolved, the patient became pregnant and stopped using metformin but continued taking bromocriptine. She gave birth to a healthy boy in August 2016. After delivery, she decided to breastfeed the baby and only took bromocriptine. After 14 months of using bromocriptine alone, her PRL level increased to 208 ng/mL and the tumor reappeared (7 mm × 8 mm × 9 mm). Interestingly, the patient's PRL level decreased from 208 ng/mL to 150 ng/mL 2 months after using combination treatment with bromocriptine and metformin. On the basis of these findings, a second bromocriptine-resistant patient was recruited. After 3 months of combined treatment with bromocriptine and metformin, the patient's PRL level decreased to 2.08 ng/mL, testosterone levels increased significantly, and the tumor size decreased. Conclusions Although more cases and investigations into the mechanisms underlying these effects are needed, these 2 cases support the hypothesis that the combination of metformin and bromocriptine might be a new treatment for resistant prolactinomas. [ABSTRACT FROM AUTHOR]

Peripartum cardiomyopathy (PPCM) is an idiopathic left ventricular dysfunction in women who are in late pregnancy or the postpartum period. PPCM is a rare but sometimes fatal disease, and mechanical circulatory support is required if heart failure is refractory to conventional therapy. A 28-year-old woman in late pregnancy was admitted to our hospital due to congestive heart failure with cardiogenic shock. Her heart rate was 200 beats per minute (sinus tachycardia), and left ventricular ejection fraction (LVEF) was 10%. Additionally, fetal heart rate decreased to 80 beats per minute. It was extremely difficult to continue her pregnancy because of decompensated heart failure and fetal asphyxia; therefore, we delivered her baby via caesarean section after initiating mechanical circulatory support. With optimal medical therapy, including bromocriptine, we were able to remove mechanical circulatory support. Additionally, LVEF improved to 42%, and she was discharged with her baby who had no growth failure. This case highlights the safety and risk of caesarean section under mechanical circulatory support, and the effectiveness of bromocriptine. < Learning objective: Mechanical circulatory support is occasionally required if heart failure is refractory to conventional medical therapy in peripartum cardiomyopathy (PPCM). Mechanical circulatory support, particularly extracorporeal membrane oxygenation needing sufficient anticoagulation, should be initiated following delivery via caesarean section because of bleeding from the uterus. Moreover, bromocriptine may be effective in improving PPCM and should be the first-line treatment in clinical practice.> [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. Aim of the study We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. Materials and methods Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells. Results Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells. Conclusions Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Catechol-O-methyltransferase (COMT), an enzyme that catalyzes the degradation of dopamine, is necessary for both motor and cognitive functions. Few studies have examined the association between COMT variants and cognition in patients with Parkinson's disease (PD).Methods: We assessed a cohort of 409 PD patients without dementia who were regularly followed for two years. The Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE) were administered at baseline and during the follow-up. The genetic variants and haplotypes of COMT, including rs6267, rs6269, rs4633, rs4818, and rs4680, were examined.Results: No association was observed between COMT genotypes and baseline cognitive function. After a mean follow-up period of 647.3 days, MMSE scores deteriorated with age. Cognitive decline correlated with age (P < 0.05) but not with the motor severity defined using UPDRS part III scores (P = 0.21). Kaplan-Meier survival analyses showed that PD patients carrying the G allele of the rs6269 variant and COMT haplotypes constituting the G allele of rs6269 showed a significantly more rapid decline in the MMSE scores over the follow-up period (log-rank test, P < 0.01). Cox proportional regression analysis adjusted for covariates revealed that among patients with PD, those carrying the high-COMT activity haplotype (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) showed a high risk of cognitive decline (hazard ratio = 3.24; P = 0.02).Conclusion: Our findings suggest that the high-COMT activity haplotype is associated with cognitive decline in patients with PD. [ABSTRACT FROM AUTHOR]

Résumé La prolactine est une hormone polypeptidique synthétisée et sécrétée par les cellules lactotropes de l’antéhypophyse. En endocrinologie, il existe quatre inhibiteurs de la prolactine : la bromocriptine, le lisuride, la cabergoline et le quinagolide. Summary Prolactin is a synthesised polypeptide hormone secreted by the lactotroph cells of the anterior pituitary. In endocrinology, there are four prolactin inhibitors: bromocriptine, lisuride, cabergoline and quinagolide. [ABSTRACT FROM AUTHOR]

The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons. [ABSTRACT FROM AUTHOR]

Cyclic and Non-cyclic Breast-pain: A systematic review on pain reduction, side effects, and quality of life for various treatments.Background: No clear systematic-review on all the various treatment regimen for (Non-) cyclical-breast-pain currently exists.Objectives: The aim of this study was to assess the various forms of therapy for treatment of breast-pain and the evidence for their effectiveness.Search Strategy: Search-terms included 'mastalgia' and 'therapy' or 'hormones' or 'nsaid' or 'psychotherapy' or 'analgesia' or 'surgery', and synonyms.Selection Criteria: The review was conducted according to the Preferred Reporting Items for Systematic-reviews and Meta-Analysis guidelines. RCT's and pro-/retrospective studies reporting on treatment of breast-pain were considered eligible. Minimal follow-up and sample-size criteria were 6 months and 10 patients respectively.Data Collection and Analysis: Data was extracted using standardized tables and encompassed number of subjects, type of breast-pain and treatment, efficacy of treatment and clinical complications/side-effects. No pooling of data could be achieved due to heterogeneity amongst studies.Main Results: Twenty-three studies were included, that reported on 2100 patients in total. Topical-Diclofenac was found to reduce pain by 58.7 and 63.3 on a Visual-Analogue-Scale (VAS) in cyclical and non-cyclical-breast-pain respectively. Persistent cyclical-breast-pain can be treated with short courses (2-6 months) of either Bromocryptine (VAS↓=25.4) or Danazol (VAS↓=33.6) as long as benefits outweigh the side-effects. Last-resort options for unresponsive and severe debilitating breast-pain include surgery in the form of bilateral mastectomy with reconstruction.Conclusions: Pain reduction in patients with breast-pain can be achieved with analgesics, hormonal-regimen and possibly surgery as a last resort. Additional studies are needed with well-described patient-characteristics, robust study set-up, and longer follow-up times. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Paeoniflorin and liquiritin are major constituents in some Chinese herbal formulas, such as Yiru Tiaojing (YRTJ) Granule (a hospitalized preparation) and Peony-Glycyrrhiza Decoction, used for hyperprolactinemia-associated disorders. Aim of the study To investigate the effect of paeoniflorin and liquiritin on prolactin secretion. Materials and methods The effect of YRTJ Granule on metoclopramide-induced hyperprolactinemia was tested in rats. Paeoniflorin and liquiritin in the YRTJ Granule extract were identified and quantified by HPLC. The effects of paeoniflorin and liquiritin on prolactin secretion were examined in prolactinoma cells that were identified morphologically and by Western blot. The concentration of prolactin was determined by ELISA. The gene expression was analyzed by Western blot. Results YRTJ Granule ameliorated metoclopramide-induced hyperprolactinemia in rats. The contents of paeoniflorin and liquiritin in YRTJ Granule were 7.43 and 2.05 mg/g extract, respectively. Paeoniflorin, liquiritin and bromocriptine (a dopamine D 2 receptor (D 2 R) agonist) decreased prolactin concentration in MMQ cells expressing D 2 R. However, the effect of liquiritin and bromocriptine was abolished in GH3 cells lacking D 2 R expression. Interestingly, paeoniflorin still decreased prolactin concentration in GH3 cells in the same manner. Furthermore, paeoniflorin suppressed prolactin protein expression, and was without effect on D 2 R protein expression in both MMQ and GH3 cells. Conclusions The present results suggest that paeoniflorin and liquiritin play a role in YRTJ Granule-elicited improvement of hyperprolactinemia. While the effect of liquiritin is D 2 R-dependent, paeoniflorin D 2 R-independently inhibits prolactin secretion in prolactinoma cells that may especially benefit the hyperprolactinemic patients who are refractory to dopaminergic therapies. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection is associated with congenital malformations in infected fetuses and severe neurological and other systemic complications in adults. There are currently limited anti-ZIKV treatment options that are readily available and safe for use in pregnancy. In this drug repurposing study, bromocriptine was found to have inhibitory effects on ZIKV replication in cytopathic effect inhibition, virus yield reduction, and plaque reduction assays. Time-of-drug-addition assay showed that bromocriptine exerted anti-ZIKV activity between 0 and 12 h post-ZIKV inoculation, corroborating with post-entry events in the virus replication cycle prior to budding. Our docking model showed that bromocriptine interacted with several active site residues of the proteolytic cavity involving H51 and S135 in the ZIKV-NS2B-NS3 protease protein, and might occupy the active site and inhibit the protease activity of the ZIKV-NS2B-NS3 protein. A fluorescence-based protease inhibition assay confirmed that bromocriptine inhibited ZIKV protease activity. Moreover, bromocriptine exhibited synergistic effect with interferon-α2b against ZIKV replication in cytopathic effect inhibition assay. The availability of per vagina administration of bromocriptine as suppositories or vaginoadhesive discs and the synergistic anti-ZIKV activity between bromocriptine and type I interferon may make bromocriptine a potentially useful and readily available treatment option for ZIKV infection. The anti-ZIKV effects of bromocriptine should be evaluated in a suitable animal model. [ABSTRACT FROM AUTHOR]

Here, a novel biomolecular-repellent electrochemical biosensor platform is fabricated with a hydrophilic material-independent poly-dopamine, Fe3 +-mediated tannic acid (TA) deposition and the branched structure of four-armed polyethylene glycol (PEG). Dopamine (DA) and TA acted as initiator anchor for surface functionalization, and PEG was then grafted on TA/pDA-coating surface via layer-by-layer (LBL) technique. The whole process of building DNA biosensor platform is optimized and characterized with scanning electron microscope (SEM), electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), contact angle measurements (CA). PEG/TA/pDA platform demonstrates excellent characteristics in terms of electrode stability and tendency to resistance to biomacromolecules adsorption. Subsequently, the gold nanoparticles with thiol-modified oligonucleotides were deposited on PEG/TA/pDA platform as enhancer to realize the reliable detection of BACA1 in PBS solution or 10% (V/V) human blood serum. Experimental results shows that charge-transfer resistance (Rct) versus target concentration is constituted from a good linear correlation from 0.1 fM to 10 pM and is associated with a limit of detection as low as 0.05 fM (S/N = 3). Advantageously, this potentially cheap and reusable assay suggests the feasible potential for diagnostic applications in clinical analysis of breast cancer. [ABSTRACT FROM AUTHOR]

Background Bromocriptine (BRC) is effective in patients with prolactinoma. However, the cytotoxic mechanism of BRC remains unknown. Methods Slices for immunohistochemical pathology were randomly selected from 37 paraffin-embedded prolactinoma tissue sections. LC3 was detected by immunohistochemistry. GH3 and MMQ cells were treated by BRC and/or rapamycin (RAPA). Cell viability and the cell cycle were measured by CCK-8 and flow cytometry, respectively. Enzyme-linked immunosorbent assay measured prolactin secretion. Protein expression was detected by Western blot or immunofluorescence. Results LC3 was significantly expressed in prolactinoma in which patients were treated exclusively with BRC. LC3 expression was negative in normal tissues and prolactinoma in which patients were not treated with BRC. Treatment with 60 μM BRC for 24 hours induced cell death in MMQ cells by up to 50%. However, 110 μM BRC was required to produce a similar effect in GH3 cells. The cell cycle was arrested at the G 0 -G 1 phase and S phase. As the concentration and time increased, the conversion ratio of LC3-I to LC3-II increased and prolactin secretion decreased. In addition, Bcl-2 and BAX expression was decreased. The cell viability, prolactin level, and G 0 -G 1 cells are similar in MMQ cells treated with RAPA and a low concentration of BRC and MMQ cells treated with a high concentration of BRC. Compared with the effects of a high concentration of BRC, treatment with RAPA and a low concentration of BRC effectively increase the conversion rate of LC3-I to LC3-II. Conclusion BRC-treated pituitary adenoma cells mainly underwent autophagic cell death rather than apoptosis. [ABSTRACT FROM AUTHOR]

The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5 mg/kg SKF81297, 0.8 mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist’s differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior. [ABSTRACT FROM AUTHOR]

In the modern biomedical and therapeutic drug monitoring technology, development of high performance sensing methods for ergoline derivative drug, bromocriptine (BC), is a critical issue due to its plasma low concentration and important function in Parkinson’s disease. The results of the protein-ligand docking simulation consistent with competitive inhibition experimental study strongly support the binding of BC to the laccase active site. Therefore, a new biosensor for direct label-free detection of BC is presented based on surface plasmon resonance (SPR) using laccase from Bacillus sp. HR03 as a recognition element. The biosensor chip surface was constructed by covalent immobilization of the laccase on a SPR carboxymethyl dextran surface. The calculated kinetic affinity (K D ) was 5.4 nM, which indicated the high affinity between BC and the immobilized laccase. The biosensor could determine BC in a linear detection range from 0.001 ng/ml to 1000 ng/ml with a lower detection limit of 0.001 ng/ml. The biosensor provided acceptable specificity with suitable recovery in simulated blood samples. This new biosensor represents a novel, fast, sensitive, economic cost effective and accurate method for the therapeutic monitoring and detection of the BC. [ABSTRACT FROM AUTHOR]

Dopamine dysregulation syndrome (DDS) has been attributed to both dopamine replacement therapies (DRT) and the mesencephalic dopaminergic lesion. The DRT reinforcement effect is due to its action on the reward system, particularly on the nucleus accumbens (NAc). This nucleus receives two major projections, a glutamatergic from the prefrontal cortex and a dopaminergic from the posterior ventral tegmental area (pVTA). The latter modulate the former within the NAc. pVTA has been demonstrated to be implicated in the motivational effect of bromocriptine (dopamine 2 receptor (D2R) agonist) in bilateral pVTA-lesioned animals. Therefore the potential implication of the metabotropic glutamate receptor 5 (mGluR5) antagonist (MTEP: 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine) on bromocriptine-induced conditioned place preference (CPP) was explored. Results showed that the administration of the MTEP blocked completely the bromocriptine-induced CPP in bilateral pVTA-lesioned rats. Both the CPP acquisition and expression were abolished. These effects are due, at least to an increase of the glutamate concentration and that of mGlu5 receptor expression in the NAc shell of the pVTA-lesioned animals. Altogether these data demonstrated the importance of the mGlu5 receptor in the bromocriptine induced-reinforcement and that DDS is probably due to DRT effect on this glutamate receptor. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most common neurodegenerative disease, which lacks disease-modifying therapeutics so far. Studies have shown that the dysfunction of the dopaminergic system is related to a variety of pathophysiology of AD, and the expression of Dopamine D2 receptor (DRD2) in the brains of AD patients and animal models is significantly downregulated, suggesting that DRD2 may represent a therapeutic target for AD. However, the strategy of targeting DRD2 for AD treatment still lacks some key experimental evidences. Here we show that DRD2 agonist Bromocriptine improved Aβ 1-42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice. For animal study, the mice have injected intracerebroventricularly (i.c.v.) with Aβ 1-42 (410 pmol/5 μl) to induced AD cognitive deficit model (Mazzola et al., 2003; van der Stelt et al., 2006). After 7 days, Bromocriptine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) or normal saline was administered intragastrically once a day for 30 days. Behavioral tests about the Y maze and Morris water maze in mice were initiated on the twenty-fourth day of drug administration for 7 days. In vivo and in vitro mechanism research revealed that Bromocriptine, via activating DRD2, promoted the recruitment of PP2A and JNK by scaffold protein β-arrestin 2, that repressed JNK-mediated transcription of proinflammatory cytokines and activation of NLRP3 inflammasome in microglia. Collectively, our findings suggest that Bromocriptine can ameliorate Aβ 1-42 induced neuroinflammation and memory deficits in mice through DRD2/β-arrestin 2/PP2A/JNK signaling axis, which provides an experimental basis for the development of Bromocriptine as a drug for AD. [ABSTRACT FROM AUTHOR]

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 (0.1 μg/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. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) infectious disease is a major public health problem worldwide; however, licensed vaccines or specific antiviral drugs against this infection are not available. To identify novel anti-DENV compounds, we screened 1280 pharmacologically active compounds using focus reduction assay. Bromocriptine (BRC) was found to have potent anti-DENV activity and low cytotoxicity (half maximal effective concentration [EC 50 ], 0.8–1.6 μM; and half maximal cytotoxicity concentration [CC 50 ], 53.6 μM). Time-of-drug-addition and time-of-drug-elimination assays suggested that BRC inhibits translation and/or replication steps in the DENV life cycle. A subgenomic replicon system was used to verify that BRC restricts RNA replication step. Furthermore, a single amino acid substitution (N374H) was detected in the NS3 protein that conferred resistance to BRC. In summary, BRC was found to be a novel DENV inhibitor and a potential candidate for the treatment of DENV infectious disease. [ABSTRACT FROM AUTHOR]

In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1 μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol–saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1–10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11–20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes. [ABSTRACT FROM AUTHOR]

Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n -alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues ( 10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds. [ABSTRACT FROM AUTHOR]

Hierarchical nanoporous AuAg (HNP-AuAg) alloy with bimodal ligament/pore size distributions is fabricated by means of selective dealloying of Al and redealloying of Ag from AuAgAl source alloy combined with annealing operation. The as-made HNP-AuAg alloy consists of interconnected hierarchical nanoporous architecture with two order ligament/pore size distributions around 100 and 10 nm in all three dimensions. Characterized by such the specific nanoporous architecture, HNP-AuAg alloy exhibits excellent electrocatalytic activities towards the simultaneous and individual oxidation of dopamine (DA) and uric acid (UA) in the absence and presence of ascorbic acid. The electrochemical sensing towards DA and UA on HNP-AuAg alloy displays fast response and low detection limit of 0.2 μM and 1.0 μM in a wide linear range of 5–335 μM and 5–425 μM, respectively. More importantly, the as-made HNP-AuAg alloy behaves long-term stability and reproducibility towards the detection of DA and UA. Along with these attractive features, HNP-AuAg shows great application potential for constructing electrochemical sensors to the detection of DA and UA. [ABSTRACT FROM AUTHOR]

Background Although prolactinomas are treated effectively with dopamine agonists, some have proposed curative surgical resection for select cases of microprolactinomas to avoid life-long medical therapy. We performed a cost-effectiveness analysis comparing transsphenoidal surgery (either microsurgical or endoscopic) and medical therapy (either bromocriptine or cabergoline) with decision analysis modeling. Methods A 2-armed decision tree was created with TreeAge Pro Suite 2012 to compare upfront transsphenoidal surgery versus medical therapy. The economic perspective was that of the health care third-party payer. On the basis of a literature review, we assigned plausible distributions for costs and utilities to each potential outcome, taking into account medical and surgical costs and complications. Base-case analysis, sensitivity analysis, and Monte Carlo simulations were performed to determine the cost-effectiveness of each strategy at 5-year and 10-year time horizons. Results In the base-case scenario, microscopic transsphenoidal surgery was the most cost-effective option at 5 years from the time of diagnosis; however, by the 10-year time horizon, endoscopic transsphenoidal surgery became the most cost-effective option. At both time horizons, medical therapy (both bromocriptine and cabergoline) were found to be more costly and less effective than transsphenoidal surgery (i.e., the medical arm was dominated by the surgical arm in this model). Two-way sensitivity analysis demonstrated that endoscopic resection would be the most cost-effective strategy if the cure rate from endoscopic surgery was greater than 90% and the complication rate was less than 1%. Monte Carlo simulation was performed for endoscopic surgery versus microscopic surgery at both time horizons. This analysis produced an incremental cost-effectiveness ratio of $80,235 per quality-adjusted life years at 5 years and $40,737 per quality-adjusted life years at 10 years, implying that with increasing time intervals, endoscopic transsphenoidal surgery is the more cost-effective treatment strategy. Conclusions On the basis of the results of our model, transsphenoidal surgical resection of microprolactinomas, either microsurgical or endoscopic, appears to be more cost-effective than life-long medical therapy in young patients with life expectancy greater than 10 years. We caution that surgical resection for microprolactinomas be performed only in select cases by experienced pituitary surgeons at high-volume centers with high biochemical cure rates and low complication rates. [ABSTRACT FROM AUTHOR]

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4–6 after administration. Pretreatment with d -cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain. [ABSTRACT FROM AUTHOR]

A series of compounds have been reported to enhance memory via the DA system and herein a heterocyclic compound was tested for working memory (WM) enhancement. 2-((benzhydrylsulfinyl)methyl)thiazole (CE-103) was synthesized in a six-step synthesis. Binding of CE-103 to the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters and dopamine reuptake inhibition was tested as well as blood brain permeation and a screen for GPCR targets. 60 male Sprague Dawley rats were divided into six groups: CE-103 treated 1–10 mg/kg body weight, trained (TDI) and yoked (YDI) and vehicle treated, trained (TVI) and yoked (YVI) rats. Daily single intraperitoneal injections for a period of 10 days were administered and rats were tested in a radial arm maze (RAM). Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT) and complexes containing the D1-3 dopamine receptor subunits were determined. CE-103 was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC 50 = 14.73 μM). From day eight the compound was decreasing WM errors in the RAM significantly at both doses tested as compared to the vehicle controls. In the trained CE-103-treated group levels of the complex containing the phosphorylated dopamine transporter (pDAT) as well as D1R were decreased while levels of complexes containing D2R and D3R were significantly increased. CE-103 was shown to enhance spatial WM and DA reuptake inhibition with subsequent modulation of D1-3 receptors is proposed as a possible mechanism of action. [ABSTRACT FROM AUTHOR]

Altered emotional experiences in response to antipsychotics may increase the burden of disease in patients with schizophrenia. In a large cross-sectional study, patients with schizophrenia completed the Subjects Reaction to Antipsychotics questionnaire (SRA) to assess whether they attributed altered emotional experiences (flattened affect or depressive symptoms) to their antipsychotics. Association with antipsychotic D 2 receptor affinity and occupancy was examined using logistic regression. We compared antipsychotic-attributed emotional experiences between patients using antipsychotic monotherapy and combination therapy. Of the 1298 included patients, 23% attributed flattened affect to their antipsychotics and 16% attributed depressive symptoms to their antipsychotics, based on the SRA. No differences were observed between antipsychotics in patients on monotherapy. We discuss that within these patients’ relatively low dose range, altered emotional experiences did not appear to relate to the level of D 2 receptor affinity of antipsychotic monotherapy. Patients using antipsychotic combination therapy (22%) were more likely to attribute depressive symptoms to their antipsychotics than patients using antipsychotic monotherapy (OR [95%CI]=1.443 [1.033–2.015]); possibly due to higher D 2 receptor occupancies as estimated by dose equivalents. [ABSTRACT FROM AUTHOR]

A silica/gold (SiO 2 /Au) cavity array microelectrode was fabricated on a gold film-coated glass slide by using highly ordered monodispersed polystyrene spheres as a template. The surface of the silica, as the upper part of the cavity, was sulfonated by 1,3-propanesultone, providing negative charges on the surface of the cavities in a media with pH > 2. The ion selectivity of the sulfonated SiO 2 /Au cavities was revealed by voltammetric response of potassium ferricyanide and methyl viologen dichloride as the electrochemical probes. Due to the electrostatic interaction, the positively charged methyl viologen cations can transport through the negatively charged SiO 2 gate and react on active sites at the bottom of the cavities, whereas the diffusion access of the negatively charged ferricyanide anions into the cavities is blocked by the SiO 2 gate. The ion selective gate of the cavities enables the electrode to selectively detect dopamine in the presence of ascorbic acid and uric acid, giving a linear range from 15 μM to 160 μM and a low detection limit of 85 nM. [ABSTRACT FROM AUTHOR]

Microporous ZnO nanorods (NRs) in situ growth on indium tin oxide (ITO) glass substrate was successfully prepared via a simple hydrothermal reaction and without porous template. The special nanostructures of ZnO were characterized by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD). The results indicated that the nanostructures of ZnO were microporous in the top plane of the hexagonal wurtzite structure and uniformly distributed on the ITO substrate. Furthermore, the sensor constructed with microporous ZnO NRs/ITO exhibited extremely high and selectively electrocatalytic activity toward the oxidation of dopamine at 0.2 V with good detection limit of 0.45 μM and wide linear range from 2 μM to 777 μM even in the presence of ascorbic acid and uric acid. [ABSTRACT FROM AUTHOR]

In most mammals, prolactin (PRL) is essential for maintaining lactation, and the suppression of PRL inhibits lactation. However, the involvement of PRL in the control of ruminant lactation is less clear, because inconsistent effects on milk yield have been observed with the short-term suppression of PRL by bromocriptine. Therefore, several experiments have been conducted to assess the galactopoietic role of PRL. In an initial experiment, cows in early lactation received daily injections of the dopamine agonist quinagolide for 9 wk. Quinagolide reduced milking-induced PRL release and caused a faster decline in milk production. Quinagolide also reduced mammary epithelial cell activity, survival, and proliferation. In goats, cabergoline, another dopamine agonist, caused a 28% decrease in milk yield the day after injection. In another experiment, cows were injected for 5 d with quinagolide, with quinagolide plus bovine PRL injected at milking time, or with vehicles only. Again, quinagolide reduced milk, protein, and lactose yields. Although PRL injections were not sufficient to restore milk yield, they tended to increase milk protein and lactose yields and increased the viability of mammary epithelial cells purified from milk. Recently, our team stimulated PRL secretion with daily injections of the dopamine antagonist domperidone for 5 wk. Milk production increased gradually and was greater in domperidone-treated cows during the last 4 wk of the treatment period. In most experiments where PRL secretion was manipulated, feed intake paralleled the changes of PRL concentration, supporting the idea that PRL increases feed intake to provide the nutrients necessary to support lactation in dairy ruminants. In late-lactation cows, quinagolide and cabergoline decreased milk production within the first day of treatment and induced more rapid changes in several markers of mammary gland involution after drying-off. In addition, quinagolide improved the resistance to intramammary infection, suggesting that PRL inhibition could be an alternative strategy for facilitating dryingoff. Prolactin appears to directly affect mammary gland functions, but mammary gland responsiveness to PRL appears to be modulated by local and systemic factors. Therefore, the modulation of the number and isoforms of the PRL receptors as well as the expression of intracellular modulators of cell signaling in the mammary gland require further investigation. In conclusion, these data, combined with those from other studies, provide a good body of evidence that PRL is galactopoietic in dairy ruminants. [ABSTRACT FROM AUTHOR]

Elite Spanish professional soccer players surprisingly showed a preponderance of an allele coding for nitric oxide synthase (NOS) that resulted in lower nitric oxide (NO) compared with Spanish endurance and power athletes and sedentary men. The present paper attempts a speculative explanation. Soccer is an "externally-paced" (EP) sport and team work dependent, requiring "executive function skills". We accept that time interval estimation skill is, in part, also an executive skill. Dopamine (DA) is prominent among the neurotransmitters with a role in such skills. Polymorphisms affecting dopamine (especially DRD2/ANKK1-Taq1a which leads to lower density of dopamine D2 receptors in the striatum, leading to increased striatal dopamine synthesis) and COMT val 158 met (which prolongs the action of dopamine in the cortex) feature both in the time interval estimation and the executive skills literatures. Our paper may be a pioneering attempt to stimulate empirical efforts to show how genotypes among soccer players may be connected via neurotransmitters to certain cognitive abilities that predict sporting success, perhaps also in some other externally-paced team sports. Graphing DA levels against time interval estimation accuracy and also against certain executive skills reveals an inverted-U relationship. A pathway from DA, via endogenous morphine and mu3 receptors on endothelia, to the generation of NO in tiny quantities has been demonstrated. Exercise up-regulates DA and this pathway. With somewhat excessive exercise, negative feedback from NO down-regulates DA, hypothetically keeping it near the peak of the inverted-U. Other research, not yet done on higher animals or humans, shows NO "fine-tuning" movement. We speculate that Caucasian men, playing soccer recreationally, would exemplify the above pattern and their nitric oxide synthase (NOS) would reflect the norm of their community, whereas professional players of soccer and perhaps other EP sports, with DA boosted by very frequent and intense practice and extra stress from public scrutiny, would potentially have their negative feedback system overwhelmed, were it not that many of them carry the C allele of the NOS3-786T/C polymorphism. Then, even very high DA would not result in so much NO as to shut the system down. We add some evolutionary speculations. [ABSTRACT FROM AUTHOR]

Summary Dopamine transporters (DATs) control neurotransmitter dopamine (DA) homeostasis by reuptake of excess DA, assisted by sodium and chloride ions. The recent resolution of DAT structure (dDAT) from Drosophila permits us for the first time to directly view the sequence of events involved in DA reuptake in human DAT (hDAT) using homology modeling and full-atomic microseconds accelerated simulations. Major observations are spontaneous closure of extracellular gates prompted by DA binding; stabilization of a holo-occluded intermediate; disruption of N82-N353 hydrogen bond and exposure to intracellular (IC) water triggered by Na2 dislocation; redistribution of a network of salt bridges at the IC surface in the inward-facing state; concerted tilting of IC-exposed helices to enable the release of Na + and Cl − ions; and DA release after protonation of D79. The observed time-resolved interactions confirm the conserved dynamics of LeuT-fold family, while providing insights into the mechanistic role of specific residues in hDAT. [ABSTRACT FROM AUTHOR]

Male sexual satiety has been associated with a decrease in dopamine levels. Spontaneous recovery of copulatory behavior begins at least 72 h after sexual satiety is reached or in the condition in which a sexually-satiated male is exposed to a new receptive female distinct from the one with which sexual satiety was reached. The aim of the present study was to explore whether dopaminergic activation by bromocriptine (BrCr) can reactivate copulatory behavior with the same sexual mate immediately after sexual satiety is reached. Male rats were divided into three groups exposed to one of the following three conditions: 1) administration of 2 mg/kg s.c. of BrCr and exposure to the same female with whom sexual satiety was previously reached; 2) administration of 0.3 mL s.c. of the vehicle solution with exposure to the same female with whom sexual satiety was reached; and, 3) exposure to a new receptive female after sexual satiety was reached. Results showed that BrCr significantly reactivated copulatory capability in sexually-satiated males with the same receptive female. In contrast, no males in the vehicle group ejaculated with the same female after reaching sexual exhaustion. Copulation was reactivated by BrCr in a way similar to that observed in untreated males exposed to a new receptive female ( i.e. , the Coolidge effect). The reversal of sexual satiety in the males treated with BrCr could be explained by its action on D2 family receptors, which promotes a reactivation of sexual motivation at a level sufficient to allow renewed copulation with the same female mate. [ABSTRACT FROM AUTHOR]