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Journal of the ASEAN Federation of... 2024There has been an increasing awareness of the effects of combining bromocriptine-QR with other medications for diabetes mellitus type 2. This study aimed to assess the... (Meta-Analysis)
Meta-Analysis Review
Efficacy and Safety of Bromocriptine-QR as an Adjunctive Therapy on Glycemic Control in Subjects with Uncontrolled Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.
INTRODUCTION
There has been an increasing awareness of the effects of combining bromocriptine-QR with other medications for diabetes mellitus type 2. This study aimed to assess the efficacy and safety of bromocriptine-QR as an adjunctive therapy for patients with uncontrolled type 2 diabetes mellitus.
METHODOLOGY
This systematic review is registered at the International Prospective Register of Systematic Reviews (CRD42022360326). Literature search was done via MEDLINE, NCBI, Google Scholar, Science Direct, Europe PMC and Cochrane Library databases. We included randomized controlled trials with participants 18 years old and above with uncontrolled type 2 diabetes mellitus. The primary outcome of interest is the efficacy and safety of bromocriptine-QR as an adjunctive therapy for glycemic control. Case reports, case series, reviews and animal studies were excluded. The risk of bias was reviewed using the Cochrane Risk of Bias tool. Meta-analysis was performed using Review Manager 5.4 and presented as a weighted mean difference and 95% confidence interval for changes from the baseline level.
RESULTS
Nine studies were included in the systematic review with a total of 2709 participants. The baseline HbA1c in the bromocriptine-QR group was 7.42% and 7.51% in the control group. The bromocriptine-QR group was favoured, outperforming the control group in terms of reducing hemoglobin A1c(HbA1c), with a statistically significant difference (weighted mean difference -0.6%; 95% CI [-0.83,-0.36]; p<0.00001). The most common side effects were nausea (33.75% vs 6.92%), fatigue (13.11% vs 5.94%), and headache (11.17% vs 6.87%).
CONCLUSION
Administration of bromocriptine-QR at a dose range of 1.6 to 4.8 mg/day as an adjunctive therapy reduced HbA1c and FBG in patients with uncontrolled type 2 diabetes mellitus (T2DM). However, there were also statistically greater odds of the occurrence of adverse events such as nausea, vomiting, and headache compared to controls.
Topics: Humans; Diabetes Mellitus, Type 2; Bromocriptine; Glycemic Control; Hypoglycemic Agents; Blood Glucose; Glycated Hemoglobin; Treatment Outcome; Drug Therapy, Combination; Dopamine Agonists
PubMed: 38863918
DOI: 10.15605/jafes.039.01.19 -
American Journal of Cancer Research 2024ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary...
Dopamine pre-treatment impairs the anti-cancer effect of integrated stress response- and TRAIL pathway-inducing ONC201, ONC206 and ONC212 imipridones in pancreatic, colorectal cancer but not DMG cells.
ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary targets and mechanisms involving targeting mitochondrial protein ClpP and antagonism of dopamine receptors D2/3 (DRD2/3). We hypothesized that dopamine, the agonist of DRD2, may counteract ONC201 or ONC206 for DRD2/3 and impair the anti-cancer effect of ONC201 or ONC206, thus protect the tumor cells from the cytotoxic effect of ONC201 or ONC206. We therefore pre-treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, and diffuse midline glioma (DMG) with dopamine, followed by treatment of ONC201, ONC206 or ONC212. We observed that 48 hours of pre-treatment with dopamine impaired the cell viability suppression effect of ONC201, ONC206 and ONC212 in pancreatic cancer cells and colorectal cancer cells. We pre-treated multiple cancer cell lines with dopamine for one week followed by ONC201, ONC206, or ONC212 treatment and performed colony assays. Pre-treatment with dopamine impaired the anti-cancer effect of ONC201 or ONC206 in pancreatic cancer and colorectal cancer. Impairment of ONC212 effect by pre-treatment with dopamine was also seen in colony assay for colorectal cancer, but not in pancreatic cancer cells by colony assay. No protection from killing by imipridones was observed with DRD2 agonist sumanirole in tumor cells, or with brain tumor cell lines pretreated with dopamine. Immunoblotting was conducted to investigate whether dopamine pre-treatment impacts signaling pathways reported to be affected by ONC201. The dopamine pre-treatment did not impact changes in ATF4, CHOP, DR5 and ClpX which were reported to be affected by ONC201. The mechanism of impairment of ONC201/206/212 effect caused by dopamine pre-treatment appears to involve upregulation of anti-apoptotic p-Bad, XIAP, FLIP and pAkt. Our results shed light on mechanisms of cancer cell protection by dopamine after imipridone treatment, heterogeneity among different tumor cell types, and suggest that effects of dopamine adaptation on tumor cells may impact on cell survival pathways in ways that may or may not depend on expression of dopamine receptors.
PubMed: 38859853
DOI: 10.62347/ZOTV8006 -
Neurobiology of Disease Jun 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
Frontiers in Neurology 2024Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists....
INTRODUCTION
Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD.
METHODS
We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists.
RESULTS
A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance ( = 0.011).
CONCLUSION
ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.
PubMed: 38841693
DOI: 10.3389/fneur.2024.1404904 -
BioRxiv : the Preprint Server For... May 2024Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males....
BACKGROUND
Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine.
METHODS
We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects.
RESULTS
Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus.
CONCLUSIONS
These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.
PubMed: 38826392
DOI: 10.1101/2024.05.20.595049 -
European Journal of Pharmacology Aug 2024Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4β2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both...
Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4β2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-β-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-β-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-β-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-β-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson's Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-β-estradiol reduces dopaminergic neuron vulnerability.
Topics: Receptors, Dopamine D3; Estradiol; Animals; Dopaminergic Neurons; Receptors, Nicotinic; Mice; Neuroprotective Agents; Female; Male
PubMed: 38821163
DOI: 10.1016/j.ejphar.2024.176678 -
Frontiers in Bioscience (Landmark... May 2024Colorectal cancer (CRC) is a major cause of mortality and morbidity. A study proved that brexpiprazole, as a novel dopamine receptor partial agonist, can also prevent...
BACKGROUND
Colorectal cancer (CRC) is a major cause of mortality and morbidity. A study proved that brexpiprazole, as a novel dopamine receptor partial agonist, can also prevent CRC cell proliferation. Therefore, clarifying the molecular mechanism of brexpiprazole is vital to developing a novel therapeutic strategy for CRC.
METHODS
The effect of brexpiprazole on human colorectal cancer cell proliferation was measured with Cell Counting Kit-8 (CCK-8) kits. Cell migration capability was measured using wound healing and transwell. Cell apoptosis was evaluated with a flow cytometer. Western blots and immunohistochemical staining were used to evaluate protein expression. The effects observed were also confirmed in xenograft models.
RESULTS
Brexpiprazole remarkably inhibited the proliferation, suppressed the migration ability, and induced apoptosis of colorectal cancer cells. Mechanism study showed that brexpiprazole exerted these effects by inhibiting the EGFR pathway. Brexpiprazole enhanced HCT116 cells' sensitivity to cetuximab, and a combination of brexpiprazole and cetuximab inhibited xenograft tumor growth .
CONCLUSIONS
Our finding suggested that brexpiprazole inhibits proliferation, promotes apoptosis, and enhances CRC cells' sensitivity to cetuximab by regulating the EGFR pathway and it might be an efficacious treatment strategy for CRC.
Topics: Humans; Colorectal Neoplasms; Thiophenes; ErbB Receptors; Animals; Cell Proliferation; Apoptosis; Cetuximab; Mice, Nude; Xenograft Model Antitumor Assays; Quinolones; Cell Movement; Cell Line, Tumor; Mice; HCT116 Cells; Mice, Inbred BALB C; Disease Progression
PubMed: 38812296
DOI: 10.31083/j.fbl2905174 -
Scientific Reports May 2024The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial...
The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial results have been published on this issue. We aimed to prove whether antipsychotics might exert adverse or protective effects against fatal outcomes derived from COVID-19. A population-based retrospective cohort study (January 2020 to November 2020) comprising inpatients (15,968 patients) who were at least 18 years old and had a laboratory-confirmed COVID-19 infection. Two sub-cohorts were delineated, comprising a total of 2536 inpatients: individuals who either had no prescription medication or were prescribed an antipsychotic within the 15 days preceding hospitalization. We conducted survival and odds ratio analyses to assess the association between antipsychotic use and mortality, reporting both unadjusted and covariate-adjusted results. We computed the average treatment effects, using the untreated group as the reference, and the average treatment effect on the treated, focusing solely on the antipsychotic-treated population. Among the eight antipsychotics found to be in use, only aripiprazole showed a significant decrease in the risk of death from COVID-19 [adjusted odds ratio (OR) = 0.86; 95% CI, 0.79-0.93, multiple-testing adjusted p-value < 0.05]. Importantly, these findings were consistent for both covariate-adjusted and unadjusted analyses. Aripiprazole has been shown to have a differentiated beneficial effect in protecting against fatal clinical outcome in COVID-19 infected individuals. We speculate that the differential effect of aripiprazole on controlling immunological pathways and inducible inflammatory enzymes, that are critical in COVID19 illness, may be associated with our findings herein.
Topics: Humans; Aripiprazole; COVID-19; Male; Female; Antipsychotic Agents; Middle Aged; Retrospective Studies; Aged; SARS-CoV-2; COVID-19 Drug Treatment; Adult; Aged, 80 and over
PubMed: 38811612
DOI: 10.1038/s41598-024-60297-y -
ENeuro Jun 2024Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely...
Amylin, a pancreatic hormone that is cosecreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are coexpressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.
Topics: Animals; Ventral Tegmental Area; Male; Dopamine; Nucleus Accumbens; Receptors, Islet Amyloid Polypeptide; Rats, Sprague-Dawley; Dietary Fats; Signal Transduction; Amylin Receptor Agonists; Rats; Sucrose
PubMed: 38806231
DOI: 10.1523/ENEURO.0133-24.2024