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Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Dec 2022Studies have revealed the neuropathological mechanism of the cognitive impairment associated with neurodegenerative diseases.However,the therapies for these cognitive... (Review)
Review
Studies have revealed the neuropathological mechanism of the cognitive impairment associated with neurodegenerative diseases.However,the therapies for these cognitive disorders are limited,and the prevalence of cognitive impairment is expected to increase significantly in the future,which proves the necessity of new therapeutic agents.In recent years,the pharmacological activity of β2-adrenergic receptor(β2-AR)has been extensively studied,which has demonstrated that β2-AR agonist has therapeutic effects on the cognitive impairment associated with several common neurodegenerative diseases,including Alzheimer's disease,vascular dementia,Parkinson's disease with dementia,and Lewy body dementia.We reviewed the neuropathological features of cognitive impairment in several common neurodegenerative diseases and expounded the pharmacological effects of β2-AR on related diseases.
Topics: Humans; Neurodegenerative Diseases; Lewy Body Disease; Cognitive Dysfunction; Alzheimer Disease; Adrenergic Agonists
PubMed: 36373635
DOI: 10.3881/j.issn.1000-503X.14469 -
Archivio Italiano Di Urologia,... Dec 2022The reasons why anticholinergic drugs or β3 adrenergic agonists are selected as treatments for overactive bladder (OAB) are unclear. The aim of this study was to...
OBJECTIVE
The reasons why anticholinergic drugs or β3 adrenergic agonists are selected as treatments for overactive bladder (OAB) are unclear. The aim of this study was to investigate the background data of female OAB patients that were prescribed anticholinergic drugs or β3 adrenergic agonists in a real-world setting.
MATERIALS AND METHODS
Between January 2013 and December 2014, 75 patients who had been diagnosed with OAB were included in this study. Administered medications, age, the persistence on treatment rate at one-year, medical history, pretreatment total Overactive Bladder Symptom Score (OABSS), pretreatment score for each OABSS factor, body mass index (BMI), and various comorbidities were evaluated retrospectively. Since there were many types of anticholinergic drugs and few patients, we grouped the patients into those that were prescribed anticholinergic drugs (group A) and those that were prescribed β3 adrenergic agonists (group B).
RESULTS
75 patients (29 in group A and 46 in group B) were included in this study. There were no significant differences in age, BMI, obesity, medical history, pretreatment total OABSS, or pretreatment score for each OABSS factor. There was a significant difference in the post-voiding residual urine volume (PVR) between the groups (group A: 22 ml, group B: 9 ml; p = 0.0252). The 1-year persistence on treatment rate was 28% in both groups.
CONCLUSIONS
There were no significant differences in clinical characteristics of patients who were prescribed anticholinergics and β3 adrenergic agonists for OAB treatment, but a marginal difference of PVR value before treatment. The 1-year persistence rates of anticholinergic drugs and β3 adrenergic agonists were considered to be almost equivalent.
Topics: Humans; Female; Urinary Bladder, Overactive; Retrospective Studies; Treatment Outcome; Cholinergic Antagonists; Adrenergic Agonists
PubMed: 36576462
DOI: 10.4081/aiua.2022.4.451 -
British Journal of Pharmacology Jun 2012The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs)] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous... (Review)
Review
The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs)] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous stimuli including cytokines and GPCR activation. This review highlights the importance of adrenoceptors and phosphoprotein phosphatases (PPP) in regulating MMPs in the cardiovascular system, which may help explain some of the beneficial effects of targeting the adrenoceptor system in tissue remodelling and will establish emerging crosstalk between these three systems. Although α- and β-adrenoceptor activation increases MMP but decreases TIMP expression, MMPs are implicated in the growth stimulatory effects of adrenoceptor activation through transactivation of epidermal growth factor receptor. Furthermore, they have recently been found to catalyse the proteolysis of β-adrenoceptors and modulate vascular tone. While the mechanisms underpinning these effects are not well defined, reversible protein phosphorylation by kinases and phosphatases may be key. In particular, PPP (Ser/Thr phosphatases) are not only critical in resensitization and internalization of adrenoceptors but also modulate MMP expression. The interrelationship is complex as isoprenaline (ISO) inhibits okadaic acid [phosphoprotein phosphatase type 1/phosphoprotein phosphatase type 2A (PP2A) inhibitor]-mediated MMP expression. While this may be simply due to its ability to transiently increase PP2A activity, there is evidence for MMP-9 that ISO prevents okadaic acid-mediated expression of MMP-9 through a β-arrestin, NF-κB-dependent pathway, which is abolished by knock-down of PP2A. It is essential that crosstalk between MMPs, adrenoceptors and PPP are investigated further as it will provide important insight into how adrenoceptors modulate cardiovascular remodelling, and may identify new targets for pharmacological manipulation of the MMP system.
Topics: Adrenergic Agonists; Adrenergic Antagonists; Animals; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Phosphoprotein Phosphatases; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Proteolysis; Receptors, Adrenergic; Signal Transduction
PubMed: 22364165
DOI: 10.1111/j.1476-5381.2012.01917.x -
PloS One 2021White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to...
White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.
Topics: Adipocytes, Beige; Adipocytes, White; Adipose Tissue, Brown; Adrenergic Agonists; Animals; Bacteremia; Dioxoles; Disease Models, Animal; Energy Metabolism; Escherichia coli; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Mice; Receptors, Adrenergic, beta-3; Thermogenesis; Toll-Like Receptors
PubMed: 34437647
DOI: 10.1371/journal.pone.0256768 -
PharmacoEconomics Oct 2022Overactive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability...
BACKGROUND
Overactive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability issues and increased anticholinergic burden, which is associated with increased risk of dementia and falls/fractures. This analysis assessed the budget impact of introducing the β-adrenergic agonist vibegron for the treatment of patients with OAB from US commercial payor and Medicare perspectives.
METHODS
A budget impact model (BIM) with a 5-year time horizon was developed using a top-down, prevalence-based approach and projected market shares for 1-million-member US commercial and Medicare plans. The BIM included vibegron, mirabegron, and anticholinergics, incorporating changes in clinical outcomes (efficacy, drug-drug interactions, anticholinergic burden (ACB), OAB-related comorbidities, and adverse events (AEs)). Costs per member per month (PMPM) and per treated member per month (PTMPM) were determined. One-way sensitivity analyses quantified the impact of changes in key variables.
RESULTS
The introduction of vibegron was associated with a modest increase in PMPM cost over 5 years of $0.12 (range for years 1‒5, $0.01‒$0.26) for commercial payors and $0.24 ($0.01‒$0.52) for Medicare (PTMPM cost: $2.70 ($0.17‒$4.85) and $3.15 ($0.19‒$5.82), respectively). Costs were partially offset by savings related to decreased third-line treatment use, yearly decreases in AE and comorbidity incidence, reduced drug-drug interactions, and reduced ACB associated with vibegron introduction. PMPM costs were most sensitive to vibegron market share assumptions, OAB prevalence, and vibegron persistence at 1 month for private payors and Medicare and additionally vibegron persistence at 12 months for Medicare.
CONCLUSIONS
Vibegron may address unmet needs in treating OAB and is a useful addition to health plans while minimizing risks of anticholinergic AEs, ACB, and drug-drug interactions, which may partially offset increased pharmacy costs.
Topics: Adrenergic Agonists; Aged; Cholinergic Antagonists; Humans; Medicare; Pyrimidinones; Pyrrolidines; United States; Urinary Bladder, Overactive
PubMed: 35881325
DOI: 10.1007/s40273-022-01163-5 -
The Tokai Journal of Experimental and... Dec 2020Breath sound parameters have been reported as useful biomarkers for evaluating the airway condition.
OBJECTIVE
Breath sound parameters have been reported as useful biomarkers for evaluating the airway condition.
METHODS
The reliability of breath sound analysis using an improved method was investigated. Eighty-three asthmatic children were included in the present study. After adjusting the 0 level based on the background noises of the breath sound spectrum, the total area under the curve of the dBm (A), the roll-off from 600-1200 Hz (Slope), the ratio of the third and fourth area to the A (A/A and B/A), and the ratio of power and frequency at 50% and 75% of the highest frequency (RPF and RPF), were evaluated before and after β agonist inhalation. Spirography and the forced oscillation technique were also used to evaluate all subjects.
RESULTS
Using the new method, A/A, B/A, RPF and RPF, were significantly increased after β agonist inhalation. The increase in A/A and B/A were significantly correlated with the increase in FEV and FEE, and the increase in RPF was reversibly correlated with that in R5-R20.
CONCLUSIONS
The spectrum curve indices using the adjusted 0 level can indicate bronchial dilation with β agonist inhalation. These parameters may be useful for the assessment of bronchial reversibility in asthmatic children.
Topics: Administration, Inhalation; Adolescent; Adrenergic Agonists; Asthma; Bronchi; Child; Dilatation, Pathologic; Female; Humans; Male; Reproducibility of Results; Respiratory Function Tests; Respiratory Sounds
PubMed: 33300590
DOI: No ID Found -
Biological Psychiatry Jun 2011Psychostimulants exert behavioral-calming and cognition-enhancing actions in the treatment of attention-deficit/hyperactivity disorder (ADHD). Contrary to early views,... (Review)
Review
Psychostimulants exert behavioral-calming and cognition-enhancing actions in the treatment of attention-deficit/hyperactivity disorder (ADHD). Contrary to early views, extensive research demonstrates that these actions are not unique to ADHD. Specifically, when administered at low and clinically relevant doses, psychostimulants improve a variety of behavioral and cognitive processes dependent on the prefrontal cortex (PFC) in subjects with and without ADHD. Despite the longstanding clinical use of these drugs, the neural mechanisms underlying their cognition-enhancing/therapeutic actions have only recently begun to be examined. At behaviorally activating doses, psychostimulants produce large and widespread increases in extracellular levels of brain catecholamines. In contrast, cognition-enhancing doses of psychostimulants exert regionally restricted actions, elevating extracellular catecholamine levels and enhancing neuronal signal processing preferentially within the PFC. Additional evidence suggests a prominent role of PFC α(2) and D1 receptors in the behavioral and electrophysiological actions of low-dose psychostimulants. These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing and therapeutic actions of psychostimulants, as well as other drugs used in the treatment of ADHD. This information may be particularly relevant for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation.
Topics: Adrenergic Agonists; Animals; Antidepressive Agents; Attention Deficit Disorder with Hyperactivity; Catecholamines; Central Nervous System Stimulants; Cognition; Humans; Monoamine Oxidase Inhibitors; Neurons; Prefrontal Cortex; Synaptic Transmission
PubMed: 20875636
DOI: 10.1016/j.biopsych.2010.06.023 -
Biochimica Et Biophysica Acta May 2001We investigated the effect of the specific beta(3)-adrenergic receptor agonist CL 316,243 (CL) on proliferation and functional differentiation of the Siberian hamster... (Comparative Study)
Comparative Study
We investigated the effect of the specific beta(3)-adrenergic receptor agonist CL 316,243 (CL) on proliferation and functional differentiation of the Siberian hamster (Phodopus sungorus) white and brown preadipocytes in primary cell culture. Proliferation of both white and brown preadipocytes was stimulated by a general beta-adrenergic agonist (isoproterenol) but not by CL. Lipolysis of differentiated white and brown adipocytes was stimulated similarly by CL with maximum effect at 10 nM. Thermogenic properties of cells were assessed by immunodetection of UCP-1, the brown adipocyte specific uncoupling protein, and measurement of cytochrome c oxidase (COx) activity as an index of mitochondrial capacity. UCP-1 content was largely increased by CL in BAT but not in WAT cultures. Basal UCP-2 mRNA levels were similar in WAT and BAT cultures and increased by both CL and isoproterenol. COx activity of BAT cultures was twice as high as that of WAT cultures but in neither cell culture system could it be increased by beta-adrenergic stimulation. We suggest (i) that white and brown preadipocyte proliferation is increased in vitro via beta1 or beta(2), but not beta(3)-adrenergic pathways, (ii) that white and brown preadipocytes represent different cell types, and (iii) that in vitro beta-adrenergic stimulation it is not sufficient to induce complete thermogenic adaptation of brown adipocytes.
Topics: Adipocytes; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Cell Differentiation; Cell Division; Cells, Cultured; Cricetinae; Dioxoles; Energy Metabolism; Lipids; Lipolysis; Phodopus
PubMed: 11389970
DOI: 10.1016/s0167-4889(01)00093-3 -
Biochemical Pharmacology Jun 2001A number of experiments have demonstrated the antiobesity effects of beta(3)-adrenergic receptor stimulation by promoting thermogenesis and/or lipolysis. While many...
Up-regulation of a thermogenesis-related gene (UCP1) and down-regulation of PPARgamma and aP2 genes in adipose tissue: possible features of the antiobesity effects of a beta3-adrenergic agonist.
A number of experiments have demonstrated the antiobesity effects of beta(3)-adrenergic receptor stimulation by promoting thermogenesis and/or lipolysis. While many studies have been performed in order to develop beta(3)-adrenergic agonists as a novel strategy in the management of obesity, more information is needed about the mechanisms involved in thermogenesis and the actions of these drugs on adipocyte differentiation. To address this, the possible thermogenic and antiadipogenic properties of Tertatolol, a beta(3)-adrenergic agonist, in a diet-induced obesity model has been tested. Animals fed on a high-fat diet gained more weight and fat mass as compared with control and high-fat fed animals treated with Tertatolol. A RT-PCR was carried out in white adipose tissue specific genes involved in thermogenesis such as uncoupling proteins (UCPs) and adipogenesis such as peroxisome proliferator-activated receptor (PPARgamma2), retinoid receptors (RXRalpha/RARalpha), and fatty acid binding protein (aP2). Levels of UCP1 mRNA were augmented in the Tertatolol-treated group as compared to non-treated high-fat fed animals, while the beta(3)-adrenergic agonist treatment significantly decreased the expression levels of aP2 and transcription factors such as PPARgamma2 and the ratio RXRalpha/RARalpha as compared to obese rats. Altogether these data suggest that the antiobesity effects of beta(3)-adrenergic agonists are not limited to the promotion of thermogenesis and/or lipolysis and support the implication that these beta(3)-adrenergic agonists also affect fat deposition by impairing adipogenesis in white adipose tissue (WAT).
Topics: Adaptor Protein Complex 2; Adaptor Protein Complex alpha Subunits; Adaptor Proteins, Vesicular Transport; Adipose Tissue; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Body Temperature; Body Weight; Carrier Proteins; Down-Regulation; Female; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; RNA, Messenger; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Transcription Factors; Uncoupling Protein 1; Up-Regulation
PubMed: 11377376
DOI: 10.1016/s0006-2952(01)00562-7 -
Alzheimer's Research & Therapy May 2021Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic...
BACKGROUND
Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3 adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits, and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well.
METHODS
CL-316,243, a specific β3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p.
RESULTS
Here, we show that β3AR agonist administration decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety, and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice.
CONCLUSIONS
Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.
Topics: Adrenergic Agonists; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mice, Transgenic; tau Proteins
PubMed: 34020681
DOI: 10.1186/s13195-021-00842-3