Dopamine receptor agonist cabergoline promotes immunogenic phenotype in human monocyte-derived dendritic cells.

Dendritic cells (DCs) are known as antigen-presenting cells that are capable of regulating immune responses. DCs and T cells can interact mutually to induce antigen-specific T-cell responses. Cabergoline, which is a dopamine (DA) receptor agonist, seems to implement anti-inflammatory properties in the immune system, and therefore in the present study the impact of a DA receptor agonist cabergoline on the monocyte-derived DCs (moDCs) was assessed. Immature moDCs were treated with lipopolysaccharide to produce mature DCs (mDCs). The expression of DCs' related surface markers namely: CD11c, HLA-DR, and CD86 was measured by utilizing of flow cytometry. Real-time PCR was the technique of choice to determine the levels at which diverse inflammatory and anti-inflammatory factors in cabergoline-treated and control mDC groups were expressed. DCs treated with cabergoline displayed a significant decrease in CD86 and HLA-DR expression, markers linked to maturation and antigen presentation, respectively. In addition, the cabergoline-mDC group showed a considerable decline in terms of the levels at which IL-10, TGF-ß, and IDO genes were expressed, and an increase in the expression of TNF-α and IL-12 in comparison to the mDC control group. Our findings revealed that cabergoline as an immunomodulatory agent can relatively shift DCs into an immunogenic state, and there is a requirement for further investigations to evaluate the effects of cabergoline-treated DCs on the T cell responses in vitro, and also in various diseases including cancer in animal models.

Modulatory effect of vitamin B6 on sex hormone receptors, thyroid, and kisspeptin/kiss1r system in the uterus of pseudopregnant bitches.

This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 µg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches.

Cabergoline targets multiple pathways to inhibit PRL secretion and increases stromal fibrosis.

OBJECTIVE: Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune cells. DESIGN AND METHODS: Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape. RESULTS: Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples. CONCLUSIONS: Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG.

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in-vitro analysis of cabergoline and Mdivi-1 co-treatment effects on the autophagy-apoptosis axis.

The complex impacts of prolonged morphine exposure continue to be a significant focus in the expanding area of addiction studies. This research investigates the effectiveness of a combined treatment using Cabergoline and Mdivi-1 to counteract the neuroadaptive changes caused by in vitro morphine treatment. The impact of Methadone, Cabergoline, and a combination of Cabergoline and Mdivi-1 on the cellular and molecular responses associated with Morphine-induced changes was studied in human Neuroblastoma (SK-N-MC) and Glioblastoma (U87-MG) cell lines that were exposed to prolong Morphine treatment. Cabergoline and Mdivi-1 combined treatment effectively influenced the molecular alterations associated with neuroadaptation in chronic morphine-exposed neural cells. This combination therapy normalized autophagy and reduced oxidative stress by enhancing total-antioxidant capacity, mitigating apoptosis, restoring BDNF expression, and balancing apoptotic elements. Our research outlines morphine's dual role in modulating mitochondrial dynamics via the dysregulation of the autophagy-apoptosis axis. This emphasizes the significant involvement of DRP1 activity in neurological adaptation processes, as well as disturbances in the dopaminergic pathway during in vitro chronic exposure to morphine in neural cells. This study proposes a novel approach by recommending the potential effectiveness of combining Cabergoline and Mdivi-1 to modulate the neuroadaptations caused by morphine. Additionally, we identified BDNF and PCNA in neural cells as potential neuroprotective markers for assessing the effectiveness of drugs against opioid toxicity, emphasizing the need for further validation. The study uncovers diverse effects observed in pretreated morphine glioblastoma cells under treatment with Cabergoline and methadone. This highlights the potential for new treatments in the DRD2 pathway and underscores the importance of investigating the interplay between autophagy and apoptosis to advance research in managing cancer-related pain. The study necessitates an in-depth investigation into the relationship between autophagy and apoptosis, with a specific emphasis on protein interactions and the dynamics of cell signaling.

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.

Effects of cabergoline and dimethylcabergoline on the sexual behavior of male rats.

RATIONALE: Cabergoline (CAB) is an ergot derivative typically prescribed for the treatment of hyperprolactinemia. It suppresses the release of prolactin through agonist actions on dopamine (DA) D2 receptors; however, it possesses binding affinity for other DA and 5-HT receptors. Side effects that exacerbate valvular heart disease can occur with high doses. OBJECTIVE: The present study examined the acute, subchronic, and chronic dose-response effects of CAB and a derivative dimethylcabergoline (DMC) which acts as an antagonist instead of agonist at 5-HT 2B receptors, on appetitive and consummatory sexual behaviors of male rats. METHODS: CAB (0, 0.03, 0.15, or 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 68 days. Sexual behavior was tested every 4 days during this period for a total of 16 trials. On the 17th trial, rats were administered their dose of CAB, and 4 h after were overdosed with sodium pentobarbital, perfused intracardially, and their brains processed for Fos immunohistochemistry. DMC (0, 0.03, 0.15, 0.3 mg/kg/ml) was administered daily to sexually experienced male rats (N = 10/dose) by oral gavage for a total of 36 days. Sexual behavior was tested every 4 days for a total of 9 trials. RESULTS: CAB increased anticipatory level changes, intromissions, and ejaculations significantly across all timepoints, with the medium and high doses being most potent. The medium and high doses also increased Fos protein significantly within the medial preoptic area, whereas in the nucleus accumbens shell, the low and medium doses decreased Fos protein but the high dose increased it significantly from control. Similar to CAB, the medium and high doses of DMC increased the number of ejaculations significantly. Rats in all drug dose groups appeared healthy for the duration of the experiments. CONCLUSIONS: Both CAB and DMC facilitate ejaculations, and CAB further facilitates measures of anticipatory sexual motivation and intromissions. These data suggest that both could be used as treatments for sexual arousal disorders and ejaculation/orgasm disorders with little or no untoward side effects at low doses.

Effects of feed energy density, daily milking frequency, and a single injection of cabergoline on behavior and welfare in dairy cows at dry-off.

Drying off dairy cows may challenge animal welfare due to high milk yields. A total of 111 loose-housed Holstein cows yielding >15 kg/d of milk were included in a 2 × 2 × 2 factorial design during dry-off to investigate the effects of reduced feeding level (normal vs. reduced energy density), reduced milking frequency (twice vs. once daily), and administration of a dopamine agonist (saline i.m. injection vs. cabergoline i.m. injection) on behavior in the home pen. During the 7 d before dry-off, cows were fed and milked according to 1 of the 4 feeding level and milking frequency combinations. Within 3 h after the last milking, cows were injected i.m. with 5 mL of either saline or a dopamine agonist (5.6 mg of cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, i.e., no preceding reduction in feeding level or milking frequency before last milking). Cows' behavior during d -1, 0, and +1 relative to the last milking was recorded via video and leg-attached sensors. Cows on the reduced energy density diet spent more time feeding and showed more attempts to feed from other cows' bins on d -1. Throughout the period of observations, cows on the reduced diet spent a lower percentage of lying time with their head raised, a higher percentage of lying time with their legs bent, and less time standing in a vigilant posture than did cows on the normal lactation diet. Reducing the daily milking frequency from 2 to 1 did not result in any clear behavioral signs of discomfort. On d 0, cows injected with cabergoline lay down longer but had their head raised for a shorter percentage of time while lying, compared with cows injected with saline. Cows injected with cabergoline also spent less time feeding than cows injected with saline on d 0, and reduced the time spent drinking from d -1 to d 0. Finally, fewer cabergoline-injected cows used the brush for self-grooming, and, among cows that did use the brush, the cows injected with cabergoline reduced the time spent using the brush from d -1 to d 0. In conclusion, cows injected with cabergoline showed several behavioral changes compared with control cows injected with saline. The behavioral changes shown by cows injected with cabergoline may be indicative of malaise during the first 24 h after injection, raising concern for animal welfare. No behavioral evidence for reduced udder pain in cows injected with cabergoline compared with control cows injected with saline was found. Drying off by reducing the energy density of the diet caused behavioral changes indicative of hunger before dry-off, whereas reducing the milking frequency had no clear effects on behavior.

Cabergoline for Lactation Inhibition After Second-Trimester Abortion or Pregnancy Loss: A Randomized Controlled Trial.

OBJECTIVE: To assess cabergoline's efficacy at decreasing breast symptoms after second-trimester abortion or pregnancy loss. METHODS: This was a double-blinded, block-randomized superiority trial comparing cabergoline 1 mg once to placebo for preventing bothersome breast engorgement after second-trimester uterine evacuation. We enrolled pregnant people at 18-28 weeks of gestation who were English- or Spanish-speaking and without contraindication to the study drug. Participants completed a validated, piloted, electronic survey at baseline and at multiple timepoints through 2 weeks postprocedure to assess breast symptoms, side effects, and bother. Our primary outcome was any breast symptoms (a composite of engorgement, milk leakage, tenderness, and need for pain relief) on day 4; we planned to enroll 80 patients to show a 30% difference in breast symptoms (80% power, α=0.049). A subgroup of participants returned for serum prolactin levels. RESULTS: After screening 150 patients from April 2021 to June 2022, we enrolled 73 participants. Baseline demographics were balanced between groups: median gestational age was 21 weeks (range 18-26 weeks), 56.2% of participants were nulliparous, 34.2% self-identified as Hispanic, and 37.0% had public insurance. At baseline, reported breast symptoms were similar between groups. Among 69 participants who returned surveys on day 4, significantly fewer participants receiving cabergoline reported any breast symptoms compared with placebo (27.8% vs 97.0%, P<.001) (primary outcome) and fewer reported significant bother (2.8% vs 33.3%, P=.001) (secondary outcome). These differences persisted through day 14. Reported incidence and severity of bother from side effects were similar between groups: most common were constipation, fatigue, and headache. Serum prolactin levels were similar at baseline. On day 4, mean serum prolactin level was 6.5 ng/mL (SD 2.2) for those who received cabergoline and 18.0 ng/mL (SD 5.9) for placebo (P=.049). CONCLUSION: Cabergoline is an effective and well-tolerated strategy to prevent breast symptoms after second-trimester abortion or pregnancy loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04701333.

Effects of feeding level, milking frequency, and single injection of cabergoline on blood metabolites, hormones, and minerals around dry-off in dairy cows.

This study aimed to investigate the effect of the different dry-off strategies based on reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.e. saline vs. cabergoline injection) on blood metabolites, hormones, and minerals around dry-off. In this experiment, 119 Holstein dairy cows were used in a 2 × 2 × 2 factorial arrangement. In the last week before dry-off, cows were allocated to 1 of the 4 possible dry-off strategies based on feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a D2 dopamine agonist (cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, e.g., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same dry cow diet and data collection continued for a week. Blood samples were collected from the coccygeal vein on d -9, -6, -5, -2, 1, 2, 5, and 7 relative to dry-off. Additionally, blood was sampled at 0, 3, and 6 h relative to injection of either cabergoline or saline, equivalent to d 0.125, 0.250, and 0.375 relative to last milking (dry-off). The reduced feeding level before dry-off caused reduced glucose and insulin concentrations as well as increased free fatty acid concentrations, particularly when reduced feeding level was combined with milking the cows 2× daily. The intramuscular injection of cabergoline caused the expected reduction in circulating prolactin concentrations. In addition, dopamine-agonist cabergoline induced an atypical simultaneous pattern of plasma metabolites (i.e., increased glucose and free fatty acid concentrations), hormones (i.e., reduced insulin and increased cortisol concentrations), and minerals (i.e., reduced calcium concentration), indicating that normal metabolic and mineral homeostatic regulations were hindered after the injection of ergot alkaloid cabergoline. In conclusion, reducing milking frequency seems the best management strategy to reduce milk production at dry-off among those tested in this study.

DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells.

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a ß-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of ß-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test ß-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of ß-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in ß-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.

Effect of the Prolactin Inhibitor Cabergoline and the Gonadotropin Releasing-Hormone Agonist Deslorelin in the Suppression of Plasma Prolactin Concentrations and Egg Laying in Quail (Coturnix japonica).

Egg binding and excessive laying frequently affect avian patients, and in many cases the treatment includes suppression of egg production. Currently, for the suppression of egg production in avian patients, a gonadotropin-releasing hormone agonist, in the form of a deslorelin implant, is often used. However, the commercially available deslorelin implants have an undesired delayed onset, as well as a potential brief increase in gonadotropin secretion after administration ("flare-up" effect) that can lead to oviposition before the actual suppression of gonadotropins. The objective of this study was to investigate whether the prolactin inhibitor cabergoline suppresses ovulation and whether it could be used to bridge the time until the onset of effect by the deslorelin implant. We measured the effect of cabergoline (30 µg/kg PO q24h × 14 days), deslorelin implants (4.7 mg SC), and a combination of both on egg laying and plasma prolactin concentrations in 37 quail (Coturnix japonica) over 6 weeks. Quail were divided into 4 groups: group DesCab (deslorelin implant and cabergoline oral; n = 9); group DesPlac (deslorelin implant and placebo oral; n = 9); group PlacCab (placebo implant and cabergoline oral; n = 9); and group PlacPlac (placebo implant and placebo oral; n = 10). Regular egg laying stopped in 100% (9/9) of birds in group DesCab and 78% (7/ 9) of birds in group DesPlac within 5 days of placing the deslorelin implant. No bird ceased egg production in group PlacCab (0/9), and 10% of birds ceased egg production intermittently in group PlacPlac (1/10). Treatment with the deslorelin implant (P < .001) and with cabergoline (P = .04) had a significant (negative) influence on plasma prolactin concentrations compared with the baseline. The interaction of deslorelin and cabergoline treatment, as well as time after initiation of treatment, did not have a significant effect on plasma prolactin concentrations. These results show that daily oral cabergoline has no significant influence on egg laying and only a minor biologically nonsignificant effect on lowering the relative plasma prolactin concentrations in quail.

Cabergoline for postpartum lactation suppression: Effect on blood pressure and pulse.

OBJECTIVE: To evaluate the effect of cabergoline on maternal blood pressure and pulse immediately postpartum. METHODS: We conducted a retrospective cohort study of 224 post-partum women who delivered at the University of Washington and did not breastfeed. Women who received 1 mg cabergoline within 48 h post-partum were compared to unexposed non-breastfeeding women. Systolic and diastolic blood pressure and pulse were assessed at 4-h intervals up to 24 h after cabergoline administration, and compared to unexposed women using delivery as the reference time point. Mean systolic and diastolic blood pressure and pulse were compared using linear regression and 95% confidence intervals, adjusting for age, indication for lactation suppression and weeks' gestation at delivery. RESULTS: Cabergoline-exposed women had lower mean systolic blood pressure at all time intervals. The maximum systolic blood pressure decrease with cabergoline was -10.88 mmHg (95% confidence interval -18.15 to -3.61) at >20-24 h. Mean diastolic blood pressure among cabergoline-exposed women decreased by -8.15 mmHg (95% confidence interval -13.94 to -2.36) at >20-24 h only. We found no significant difference in maternal pulse. Cabergoline was well tolerated with no adverse effects observed. CONCLUSION: Cabergoline has minimal clinically-relevant hemodynamic effects and was well tolerated among normotensive postpartum women.

Cabergoline, a long-acting dopamine agonist, attenuates L-dopa-induced dyskinesia without L-dopa sparing in a rat model of Parkinson's disease.

Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.

Effects of dietary and milking frequency changes and administration of cabergoline on clinical udder characteristics in dairy cows during dry-off.

We investigated the effects of 2 diet energy densities [normal lactation diet (NORM) vs. energy-reduced diet (REDU), both fed for ad libitum intake] and 2 daily milking frequencies [twice (2×) vs. once (1×)] during 1 week before the dry-off day, as well as effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale, Libourne, France; labelled for use only with abrupt dry-off, e.g. no reduction in diet energy density or milking frequency before the last milking] or saline (SAL) following the last milking, on clinical udder characteristics of Holstein cows. During a week before and after the last milking, the following measures were recorded: palpation-based udder firmness and soreness; image-based hock-hock distance; responsiveness to mechanical udder stimulation and degree of udder fill measured with a dynamometer. Before the last milking, REDU cows displayed lower odds of having a firm udder and lower degree of udder fill, as well as lower responsiveness to mechanical udder stimulation, than NORM cows. After the last milking, REDU cows displayed shorter hock-hock distance compared with NORM cows. The effects of milking frequency on the clinical udder characteristics were unclear. Within 24 h following injection, CAB cows showed lower odds of having a firm udder, shorter hock-hock distance, and lower degree of udder fill than SAL cows, irrespective of treatment group before dry-off. In this study, reducing diet energy density prior to dry-off, and to some extent administering the dopamine agonist cabergoline after the last milking, resulted in fewest clinical udder changes.

Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Pilot Study.

INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.

ACT001 reverses resistance of prolactinomas via AMPK-mediated EGR1 and mTOR pathways.

Dopamine agonist (DA) is the first choice for the treatment of prolactinomas, and drug resistance is unavoidable during treatment due to the heterogeneity of tumors. The two prolactinoma cell lines (GH3 cells and MMQ cells) were found to have different sensitivity and responding modes to the cabergoline (CAB) and bromocriptine (BRC). In this research, we disclosed the capability of ACT001, a derivative of parthenolide analogs, to activate AMPK by increasing the intracellular reactive oxygen species (ROS) level and AMP/ATP ratio to reverse DA resistance through dual pathways in prolactinoma cells. The results indicated that ACT001 could reverse the CAB resistance in GH3 cells by inhibiting the mTOR signaling pathway, inducing cell death through autophagy, and reverse the BRC resistance in MMQ cells by activating the EGR1 signaling pathway, inducing cell death through apoptosis. Our results suggested that ACT001 is a promising therapeutic compound for treating DA-resistant prolactinomas.

Cabergoline possesses a beneficial effect on blood-brain barrier (BBB) integrity against lipopolysaccharide (LPS).

Sepsis is a disease induced by severe systemic inflammation and contributes to multiple acute organic dysfunctions. It is reported that disrupted blood-brain barrier (BBB) integrity is involved in sepsis-associated encephalopathy (SAE), which can be alleviated by repairing the damaged tight junction structure. Cabergoline is a specific dopamine D2 receptor agonist developed to treat Parkinson's disease and hyperprolactinemia and is reported to exert promising anti-inflammatory properties. The present study aimed to explore the beneficial effect of Cabergoline for the treatment of sepsis. In the animal experiments, mice were separated into 4 groups: sham, LPS (5 mg/kg), Cabergoline (0.1 mg/kg/day), and Cabergoline+LPS. We found that the increased neurological deficits, disrupted BBB integrity, elevated production of inflammatory factors, and declined expression level of zonula occludens-1 (ZO-1) were observed in lipopolysaccharide (LPS)-treated mice, all of which were significantly reversed by the administration of Cabergoline. In the in vitro model, human brain microvascular endothelial cells (HBMECs) were challenged with 1 µg/mL LPS in the presence or absence of Cabergoline (10, 20 µM) for 24 hours. The elevated cell permeability Papp value of fluorescein disodium across the HBMECs monolayer and declined trans-endothelial electrical resistance (TEER) in the LPS-treated HBMECs were significantly alleviated by Cabergoline, accompanied by the upregulation of ZO-1. In addition, wnt1 and ß-catenin were found downregulated, which was reversed by Cabergoline. Importantly, the protective benefits of Cabergoline were all abolished by the overexpression of Dickkopf 3 (DKK3). Taken together, our data reveal that Cabergoline possessed a protective effect on BBB integrity against LPS.

Therapeutic activity of sarpogrelate and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes.

BACKGROUND: Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. METHODS: Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. RESULTS: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method. CONCLUSIONS: The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

Shrinkage by the third month predicts long-term response of macroprolactinoma after cabergoline.

OBJECTIVE: Transsphenoidal surgery (TSS) is mainly indicated in prolactinomas when dopamine agonist treatment fails. However, there is no established early predictor of cabergoline (CBG) response. The present study was aimed to identify predictors of CBG resistance in order to select patients who may benefit from early TSS. DESIGN: Retrospective longitudinal study. METHODS: We reviewed the medical record of patients diagnosed with prolactinoma after 2010. Inclusion criteria: macroprolactinomas under CBG treatment with serial prolactin levels and MRI before treatment and 3 and 12 months afterwards. The main outcome was tumour size shrinkage ≥ 50% (using the two largest diameters in sagittal view) after 12 months of CBG (TS_50). The capacity of the most important clinical and biochemical variables in predicting the main outcome was examined. RESULTS: A total of 185 prolactinomas where included: 124 (67.0%) were microadenomas and 61 (33.0%) were macroadenomas of which 27 patients meet de inclusion criteria; median age (42.5 years; (IQR: 28.0)). The median follow-up was (67.5 months; (IQR: 30.2)). Ten patients (37.0%) underwent surgery after more than 1 year of CBG. The volume reduction at the first MRI (3-4 months) was the unique valuable predictor: (OR: 1.16 (95% CI: 1.02-1.32)) of TS_50. A tumour volume shrinkage of ≥ 30% in the first 3-4 months of CBG therapy predicts TS_50 with an AUC (0.95 (CI: 0.76-0.99)). CONCLUSION: Tumour shrinkage in the first 3-4 months after starting treatment with CBG is a good tool for predicting the long-term response and can help clinicians to take more appropriated and personalized decisions.

Brusatol Inhibits Tumor Growth and Increases the Efficacy of Cabergoline against Pituitary Adenomas.

Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.