Regulatory roles of dopamine D2 receptor in milk protein production and apoptosis in mammary epithelial cells.

Dopamine D2 receptors (D2Rs) play crucial roles in regulating diverse physiological functions of the central nervous system and peripheral organs. D2Rs are also expressed in mammary glands. However, which cell types express D2Rs and whether they are involved in milk production remains unclear. The present findings revealed that D2Rs are expressed in the apical regions of the lateral membranes of mammary epithelial cells (MECs) in lactating mice. We also investigated the effects of the D2R agonist bromocriptine and/or antagonist domperidone on intracellular cAMP levels, milk protein production, and apoptosis in a lactation culture model of MECs that produce major milk components like lactating MECs in vivo. We found that bromocriptine decreased intracellular cAMP levels, whereas domperidone dose-dependently neutralized this effect. Bromocriptine also inhibited casein and lactoferrin production and suppressed activities of STAT5 and glucocorticoid receptors (GRs). Domperidone neutralized the inhibition of casein production as well as STAT5 and GR inactivation induced by bromocriptine. Furthermore, D2R activation by bromocriptine induced apoptosis and inactivated ERK, a signaling molecule responsible for promoting cell proliferation and survival. Domperidone attenuated ERK inactivation and apoptosis induced by bromocriptine. These findings suggest that D2Rs play regulatory roles in milk protein production and apoptosis in MECs.

Evaluation of bromocriptine and plumbagin against the monogenean Rhabdosynochus viridisi: Computational drug repositioning and in vitro approaches.

Monogeneans are parasitic platyhelminths that can harm the health of farmed fish. Few treatments are available against monogeneans, and the incentive to develop new antiparasitic agents is similar or even lower than the incentive for neglected parasitic diseases in humans. Considering that searching for and developing new antimonogenean compounds may require enormous investments of time, money, and animal sacrifice, the use of a computer-guided drug repositioning approach is a reasonable alternative. Under this context, this study aimed to evaluate the effectiveness of plumbagin and bromocriptine against adults and eggs of the monogenean Rhabdosynochus viridisi (Diplectanidae). Plumbagin is a phytochemical compound that has recently emerged as a potent antimonogenean; however, further investigation is required to determine its effects on different monogenean species. Bromocriptine was selected through a computational approach that included molecular docking analyses of 77 receptors of monogeneans (putative drug targets) and 77 ligands (putative inhibitors). In vitro experiments showed that bromocriptine does not exhibit mortality at concentrations of 0.1, 1, and 10 mg/L whereas plumbagin at 2 and 10 mg/L caused 100% monogenean mortality after 3 h and 30 min, respectively. The most effective concentration of plumbagin (10 mg/L) did not completely inhibit egg hatching. These findings underscore plumbagin as a highly effective agent against adult monogeneans and highlight the need for research to evaluate its effect(s) on fish. Although computational drug repositioning is useful for selecting candidates for experimental testing, it does not guarantee success due to the complexity of biological interactions, as observed here with bromocriptine. Therefore, it is crucial to examine the various compounds proposed by this method.

Sleep and local field potential effect of the D2 receptor agonist bromocriptine during the estrus cycle and postpartum period in female rats.

BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Comparing pyridoxine with dopaminergic agonists (cabergoline and bromocriptine): Unveiling the strategy for lactation inhibition - A systematic review of clinical trials.

This systematic review aims to evaluate the efficacy and safety of Pyridoxine compared to Dopaminergic agonists (cabergoline and bromocriptine) in post-partum lactation inhibition. Cochrane Central, PubMed/MEDLINE, Cochrane Central, ScienceDirect, ClinicalTrials.gov, Web of Science, CINAHL and Google Scholar, covering the period from inception to November 2023. Additionally, the bibliographies of included articles and previous meta-analyses were screened for any relevant articles. The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The outcomes of interest encompassed inhibition of lactation, breast pain/tenderness, breast engorgement, milk secretion, fever, mastitis, prolactin level and adverse events related to pyridoxine, cabergoline and bromocriptine. Methodological quality assessment was conducted using the Cochrane risk of bias assessment tool for rigorous evaluation. Three clinical trials assessed the effectiveness of pyridoxine and dopaminergic agents (cabergoline and bromocriptine) for lactation inhibition. It was assessed by using different assessment methods such as a scale for milk secretion, serum prolactin levels, and questionnaires for assessing breast engorgement, breast pain, and milk leakage. On the global assessment of the therapeutic efficacy of dopaminergic agents, it was found that there was significant inhibition of lactation as compared to pyridoxine (p < 0.001). In conclusion, this systematic review contributes significant insights into lactation inhibition interventions. Dopaminergic agonists, specifically cabergoline and bromocriptine, stand out as more effective and tolerable choices compared to Pyridoxine. These findings provide a foundation for informed clinical decisions and underscore the need for careful consideration of lactation inhibition strategies in diverse clinical contexts.

Characterization of Leptin Secretion in Premenopausal Obese Women Treated with Bromocriptine.

Leptin, a hormone secreted by adipose tissue, is primarily responsible for inhibiting hunger and maintaining energy balance. Improper leptin secretion may result in hyperleptinemia (excess secretion of leptin) or leptin resistance, both of which contribute to obesity. Diagnosing abnormal leptin secretion may help treat this underlying cause of obesity. Therefore, continuous monitoring of the level of leptin may help characterize its secretion dynamics and also help devise an appropriate treatment. In this research, we consider leptin hormone concentration data taken over a 24 hour time period from eighteen healthy premenopausal obese women before and after treatment with a dopamine agonist, bromocriptine, and deconvolve the observed leptin hormone levels to estimate the number, timing, and magnitude of the underlying leptin secretory pulses. We find that there is an overall decrease in leptin secretion, particularly during sleep, but the changes in the secretory and clearance rates, and the number of pulses underlying the secretion process are not statistically significant.Clinical relevance- This work seeks to understand the effect of bromocriptine on leptin secretory dynamics and will help further current understanding of the effect of bromocriptine in relation to obesity.

Freeze-dried powder of daylily bud improves bromocriptine-induced lactation disorder in rats via JAK2/STAT5 pathway.

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.

Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis.

Objective: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. Methods: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue® Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. Results: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. Conclusion: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.

Antipyretic Efficacy of Bromocriptine in Central Fever: an Exploratory Analysis.

BACKGROUND: 'Central' fevers are thought to result from disruption of hypothalamic thermoregulatory pathways following severe brain injuries. Bromocriptine, due to its central dopamine receptor agonism, has been hypothesized to have antipyretic effect in this setting. However, clinical evidence for this off-label use is limited to a few case reports. In this retrospective cohort study, we analyzed the effect of bromocriptine administration on body temperature in acute brain injury patients with suspected central fever. METHODS: We screened a cohort of adult patients that received bromocriptine in the neurologic-intensive care unit of a tertiary care hospital between January 2018 and December 2021. Indication of central fever was ascertained by review of clinical documentation. A generalized additive mixed model (GAMM) was used to model temperature as a function of time relative to bromocriptine initiation. We adjusted for potential confounding due to the following covariates: temperature recording method (invasive vs surface), concurrent antipyretic administration within 8 h, and surface cooling device use within 4 h of temperature measurement. Temperature-time function was modeled using a cubic spline with k = 10 knots. RESULTS: A total of 33 patients were included in the analysis (14 women; mean age: 50 y, standard deviation 14 y). Median dose of bromocriptine was 7.5 mg (range 2.5-40) for a median of 13 d (range 5-160). Age and sex did not impact the function of temperature over time. Predicted temperatures were significantly (p < 0.05) higher by 0.4 °C with invasive compared to surface recording methods, lower by 0.2 °C in the presence of cooling device use and lower by 0.1 °C with concurrent antipyretic use. On adjusted analysis with the GAMM, there was decline (p < 0.05) in temperature following bromocriptine initiation by - 0.3 °C at 24 h, - 0.5 °C at 48 h, and - 0.7 °C at 72 h. CONCLUSIONS: Bromocriptine use was associated with modest but statistically significant decline in temperature, with nadir at 72 h post initiation. The findings provide a data driven basis for prospective evaluation.

Co-administration of bromocriptine and corticosterone produces short- and long-lasting reduction in intake of high-fat food in male rats.

Dopaminergic and glucocorticoid activity has been associated with reduced food consumption; however, their possible synergic action has not yet been studied. With the aim of examining the effect of the co-administration of the dopamine receptor D2 agonist bromocriptine and corticosterone on palatable food intake, male Wistar rats were administered either bromocriptine (1 mg/kg), corticosterone (2 mg/kg), bromocriptine + corticosterone (1 mg + 2 mg/kg) or a vehicle, with a fifth group used as a control. In all cases, substances were administered 30 min before exposure to standard food or palatable food, the latter high in carbohydrates [high carbohydrate food (HCF), 75%] or high-fat food (HFF, 67%). Food consumption and body weight were recorded daily. Results showed higher consumption of standard food but lower consumption of HCF and HFF in the groups that received bromocriptine, alone or in combination. In general, lower total kcal intake was observed in the bromocriptine and bromocriptine + corticosterone groups during the period of pharmacological treatment and following re-exposure to palatable food. The low HFF intake in the bromocriptine + corticosterone group persisted 10 days after the pharmacological treatment was interrupted. This effect suggests plastic changes in either the mechanisms involved in the incentive value of palatable food - particularly foods with high-fat content - or those that regulate lipid metabolism. Our findings suggest that homeostatic and reward mechanisms could be influenced by the co-participation of the dopaminergic and hypothalamic-pituitary-adrenal systems, and the macronutrient content of food.

Wheat ergot fungus-derived and modified drug for inhibition of intracranial aneurysm rupture due to dysfunction of TLR-4 receptor in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a form of dementia that strikes elderly people more frequently than it does younger people. The cognitive skills and memory of Alzheimer's sufferers continue to deteriorate over time. Recent studies have shown that patients with AD have greater amounts of inflammatory markers in their bodies, which suggests that inflammation occurs early on in the progression of the disease. There is a possibility that Aß oligomers and fibrils can be recognised by TLRs, in addition to the microglial receptors CD14, CD36, and CD47. When Aß binds to either CD36 or TLR4, it sets off a chain reaction of inflammatory chemokines and cytokines that ultimately results in neurodegeneration. Diabetes and Alzheimer's disease have both been recently related to TLR4. The activation of TLR4 has been connected to a variety of clinical difficulties that are associated with diabetes, in addition to the internal environment of the body and the microenvironment of the brain. TLR4 inhibitors have been shown in clinical investigations to not only lessen the likelihood of getting sick but also to increase the average longevity. RESULT: In this work we used molecular docking and molecular dynamics modelling to investigate the effectiveness of FDA-approved antidiabetic plant derived drugs in combating the TLR4 receptor. Molecular docking experiments were used to make a prediction regarding the most important interactions involving 2-Bromoergocryptine Mesylate. With a binding affinity of -8.26 kcal/mol, it stood out from the other candidates as the one with the greatest potential. To verify the interaction pattern that takes place between 2-Bromoergocryptine Mesylate and the TLR4 receptor, a molecular dynamic simulation was run at a time scale of 150 nanoseconds. Because of this, 2-Bromoergocryptine Mesylate was able to make substantial contact with the active site, which led to increased structural stability during the process of the complex's dynamic development. CONCLUSION: As a result of this, the results of our research may be relevant for future research into the efficacy of 2-bromoergocryptine mesylate as a potential lead treatment for TLR4 receptors in intracranial aneurysm rupture in AD.

Dopamine D2 receptor agonist Bromocriptine ameliorates Aß1-42-induced memory deficits and neuroinflammation in mice.

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 Aß1-42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice. For animal study, the mice have injected intracerebroventricularly (i.c.v.) with Aß1-42(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 ß-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 Aß1-42 induced neuroinflammation and memory deficits in mice through DRD2/ß-arrestin 2/PP2A/JNK signaling axis, which provides an experimental basis for the development of Bromocriptine as a drug for AD.

Prolactin Inhibition in Peripartum Cardiomyopathy: Systematic Review and Meta-analysis.

Heart failure (HF) is one of the leading causes of maternal mortality and morbidity in the United States. Peripartum cardiomyopathy (PPCM) constitutes up to 70% of all HF in pregnancy. Cardiac angiogenic imbalance caused by cleaved 16kDa prolactin has been hypothesized to contribute to the development of PPCM, fueling investigation of prolactin inhibitors for the management of PPCM. We conducted a systematic review and meta-analysis to assess the impact of prolactin inhibition on left ventricular (LV) function and mortality in patients with PPCM. We included English language articles from PubMed and EMBASE published upto March 2022. We pooled the mean difference (MD) for left ventricular ejection fraction (LVEF) at follow-up, odds ratio (OR) for LV recovery and risk ratio (RR) for all-cause mortality using random-effects meta-analysis. Among 548 studies screened, 10 studies (3 randomized control trials (RCTs), 2 retrospective and 5 prospective cohorts) were included in the systematic review. Patients in the Bromocriptine + standard guideline directed medical therapy (GDMT) group had higher LVEF% (pMD 12.56 (95% CI 5.84-19.28, I2=0%) from two cohorts and pMD 14.25 (95% CI 0.61-27.89, I2=88%) from two RCTs) at follow-up compared to standard GDMT alone group. Bromocriptine group also had higher odds of LV recovery (pOR 3.55 (95% CI 1.39-9.1, I2=62)). We did not find any difference in all-cause mortality between the groups. Our analysis demonstrates that the addition of Bromocriptine to standard GDMT was associated with a significant improvement in LVEF% and greater odds of LV recovery, without significant reduction in all-cause mortality.

Review of Randomized Controlled Trials in Patients with Peripartum Cardiomyopathy.

INTRODUCTION: Peripartum cardiomyopathy (PPCM) is a rare but potentially lifethreatening disease, defined as idiopathic cardiomyopathy occurring towards the end of pregnancy or in the months following delivery, abortion or miscarriage. We aim to raise awareness of this condition and give an overview of current knowledge as well as an insight and comparison of clinical trials focusing on randomized controlled trials. MATERIAL AND METHODS: Systematic literature searches were conducted using PubMed up to December 2021. Studies published involving clinical trials and interventions in women with PPCM after 1970 were selected. RESULTS: Randomized controlled trials have shown that the addition of Bromocriptine to standardized heart failure therapy improves outcome in terms of recovery of Left Ventricular Ejection Fraction (LVEF), symptoms and death. Bromocriptine 2.5 mg twice daily for two weeks followed by 2.5 mg once daily for six weeks had the best trend and outcome. The addition of Levosimendan to standardized heart failure therapy had no effect, whereas the addition of Selenium improved heart failure symptoms but did not reduce risk in terms of unrecovered LVEF or death. One prospective study showed potential usage of TNF-alfa inhibitors, but was never tried in a randomized clinical trial. CONCLUSION: PPCM is a rare and potentially fatal disease. New insights on pathophysiology, genetics and clinical studies, particularly randomized controlled trials, have shown that the addition of Bromocriptine has a beneficial effect in terms of improved LVEF and death. However, some clinical studies have shown promising results using anti-inflammatory pharmacological agents with an improvement in LVEF. We suggest that targeting an anti-inflammatory route may prove beneficial in patients with PPCM. However, further research is highly warranted.

[Restriction of breastfeeding in the early postnatal period leads to metabolic and endocrine disorders in eighteen-month-old male rats.]

Breastfeeding deficiency in the early postnatal period can lead to metabolic and hormonal disorders in adulthood. However, there are no studies on the effect of starvation in early ontogeny on metabolic and hormonal parameters in aging animals. The effect of such starvation on the functions of the endocrine system has not been practically studied. The aim of this work was to study how interruption of lactation in lactating female rats (19-21 days of postnatal development of rat pups) affects metabolic parameters, glucose tolerance, insulin sensitivity, and hormonal status of the gonadal and thyroid axes in their offspring, 18-month-old male rats. Inhibition of lactation was induced by treating female rats with bromocriptine (10 mg/kg/day). It has been shown that aging male rats with partial deprivation of breastfeeding have characteristic signs of the metabolic syndrome, such as the increased body weight and adipose tissue, impaired glucose tolerance, insulin resistance, and hyperleptinemia. They have reduced levels of testosterone and thyroid hormones, increased levels of thyroid-stimulating hormone, reduced steroidogenic response to gonadoliberin and a decrease in thyroliberin stimulating effect on thyroxine levels. Thus, short-term deprivation of breastfeeding caused by bromocriptine-induced inhibition of lactation in lactating females leads to the development of metabolic syndrome and hormonal dysregulation of the reproductive and thyroid systems in 18-month-old male rats.

The Comparative Pharmaco- and Histokinetics of the Therapeutic Dose of Estradiol Valerate and Bromocriptine in Common Quails.

The current study is aimed at examining the overall effects of steroids on the tissues of organisms and pharmacotherapeutics and pharmaco-histokinetics of several steroids, including Bromocriptine as mesylate and estradiol valerate in common quails (Coturnix coturnix). A total of 100 birds were used for pharmaco-histokinetics. The research was carried out in two separate trials, one during the fall season and the other during the spring season. Each experiment lasted for five, ten, fifteen, and twenty days. Each study group used 20 birds while basing their experiments on a control group of 5. At the stretch of five, ten, fifteen, and twenty days in each season, therapeutic dosages were administered to a sum of two groups representing two separate steroid trial groups. Each steroid was administered to each bird in a therapeutic dose, which was three drops administered twice daily. Clinical symptoms include despondency, sluggishness, and variations in weight and temperature that almost all treated birds display. However, only in trials conducted in the fall was a sizable degree of body enlargement in one treated bird noticed. The winter testing showed a mortality rate. Four birds have died in the twenty-day group. One bird died when treated with estradiol valerate, and three birds died treated with Bromocriptine as mesylate. Both the male and female birds showed signs of having lost some of their body weight. The treated birds' kidney, stomach, hearts, and livers exhibited some edema. In comparison, almost all birds show enteritis, which indicates that steroids mainly affect the intestine. There were apparent differences in the histological analysis of heart and skeletal muscle and some treated birds with the control group. The kidney, liver, and intestine show the major histopathological change in all treated birds.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body's systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3ß, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1ß, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3ß (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1ß, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Therapeutic potential of dopamine agonists in the treatment of type 2 diabetes mellitus.

Diabetes is a global health concern that has affected almost 415 million people globally. Bromocriptine is a dopamine D2 agonist, which is a Food and Drug Administration (FDA)-approved drug to treat type 2 diabetes mellitus (T2DM) patients. However, it is considered that a novel treatment therapy is required which can be used in the treatment of diabetes with or without other antidiabetic agents. Dopamine agonists are usually used in neurological disorders like Parkinson's disease (PD), restless leg syndrome, and hyperprolactinemia. However, dopamine agonists including bromocriptine and cabergoline are also effective in reducing the glycemic level in T2DM patients. Bromocriptine was formerly used for the treatment of PD, hyperprolactinemia, and restless leg syndrome, but now it is used for improving glycemic levels as well as reducing free fatty acids and triglycerides. In addition, cabergoline has been found to be effective in glycemic control, but this drug is yet to be approved by the FDA due to its limitations and lack of study. Findings of the clinical trials of bromocriptine have suggested that it reduces almost 0.4-0.8% glycated hemoglobin and cardiovascular risk by 40% in insulin-resistant patients. Moreover, the safe use of bromocriptine in obese T2DM patients makes it a more attractive option as it causes weight loss. Indeed, bromocriptine is a novel therapy for T2DM patients, as its mechanism of action is unique in T2DM patients with minimal adverse effects. This review summarizes the potential of dopamine agonists in the treatment of T2DM.

The Inhibitory Effect of Selected D2 Dopaminergic Receptor Agonists on VEGF-Dependent Neovascularization in Zebrafish Larvae: Potential New Therapy in Ophthalmic Diseases.

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D2 dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl2) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D2 dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl2 followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl2 treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl2-derived upregulation of vegfaa expression. The present results suggest that the D2 receptor agonists can be considered as a new direction in research for antiangiogenic therapy.

Amelioration of oxidative stress utilizing nanoemulsion loaded with bromocriptine and glutathione for the management of Parkinson's disease.

Parkinson's disease (PD) is triggered by the formation of free radicals in dopaminergic neurons, which results in oxidative stress-induced neurodegeneration. The objective of the work was to relieve oxidative stress by employing intranasal delivery of Bromocriptine Mesylate (BRM) and Glutathione (GSH) loaded nanoemulsion for the better management of PD. The depth of permeation of the nanoemulsion was assessed through confocal laser scanning microscopy (CLSM) which revealed higher nanoemulsion permeation in contrast to suspension. Biocompatibility of nanoemulsion was confirmed by nasal cilio toxicity study. The DPPH study showed that the nanoemulsion had significant antioxidant activity. Biochemical estimation studies in Wistar rats were carried out in order to determine the effect of nanoemulsion on oxidative stress. The levels of GSH, superoxide dismutase (SOD), and catalase (CAT) were significantly enhanced; and the level of thiobarbituric acid reactive substances (TBARS) was significantly reduced after the intranasal administration of nanoemulsion in the haloperidol-induced model of PD. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also determined which reduced significantly after the administration of nanoemulsion. The oxidative stress levels were lowered with nanoemulsion, showing the combined antioxidant capability of BRM and GSH. The neuroprotective effect of the prepared nanoemulsion was confirmed by histopathological studies. Pharmacokinetic study revealed a higher concentration of BRM and GSH in the brain of Wistar rats after intranasal administration of nanoemulsion with a higher Brain/Plasma ratio. A higher value of AUC(0-8) of nanoemulsion in the brain after intranasal administration revealed that BRM and GSH remained in the brain for a longer period due to sustained release from nanoemulsion. According to the findings, BRM and GSH loaded nanoemulsion has the potential to provide a combined and synergistic anti-oxidant effect for efficient management of PD.

Maternal prolactin levels during late pregnancy and nurturing behavior of offspring in mice.

Elucidating the mechanisms underlying nurturing and neglect behaviors is meaningful but challenging. Recently, we found that CIN85-deficient mice had reduced pituitary hormone prolactin secretion during late pregnancy, and their pups later showed an inhibited nurturing behavior. To examine whether this phenomenon could be reproduced in normal mice and not just CIN85-deficient mice, we investigated the nurturing behavior of offspring born to mothers whose blood prolactin levels had been reduced by bromocriptine administration during late pregnancy. First, to determine when bromocriptine treatment should be started, we investigated the detailed changes in blood prolactin levels in late pregnancy in mice, resulting in the identification of the prepartum prolactin surge. Furthermore, prolactin receptors in the fetal hypothalamus were expressed to the same extent as in the adult hypothalamus. Treatment with bromocriptine decreased the plasma concentrations of prolactin to the basal range throughout late pregnancy. However, against expectations, the proportion of the resultant pups exhibiting nurturing behaviors as adults was as high as that in the mice without bromocriptine treatment. In conclusion, the elimination of prolactin secretion during late pregnancy alone does not induce neglect-like behavior in offspring, suggesting that CIN85-deficient mice appear to involve another factor due to CIN85 deficiency besides prolactin deficiency.