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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 -
European Journal of Pharmacology Nov 2023It was suggested that impaired β-adrenergic relaxation in spontaneously hypertensive rats (SHR) might contribute to their high blood pressure (BP). Our study was...
It was suggested that impaired β-adrenergic relaxation in spontaneously hypertensive rats (SHR) might contribute to their high blood pressure (BP). Our study was focused on isoprenaline-induced dilatation of conduit femoral or resistance mesenteric arteries and on isoprenaline-induced BP reduction in SHR and Wistar-Kyoto rats (WKY). We confirmed decreased β-adrenergic relaxation of SHR femoral arteries due to the absence of its endothelium-independent component, whereas endothelium-dependent component of β-adrenergic smooth muscle relaxation was similar in both strains. Conversely, isoprenaline-induced relaxation of resistance mesenteric arteries was similar in both strains and this was true for endothelium-dependent and endothelium-independent components. We observed moderately reduced sensitivity of SHR mesenteric arteries to salmeterol (β-adrenergic agonist) and this strain difference disappeared after endothelium removal. However, there was no difference in mesenteric arteries relaxation by dobutamine (β-adrenergic agonist) which was independent of endothelium. The increasing isoprenaline doses elicited similar BP decrease in both rat strains, although BP sensitivity to isoprenaline was slightly decreased in SHR. The blockade of cyclooxygenase (indomethacin) and NO synthase (L-NAME) further reduced BP sensitivity to isoprenaline in SHR. On the other hand, salmeterol elicited similar BP decrease in both strains and the blockade of cyclooxygenase and NO synthase increased BP sensitivity to salmeterol in SHR as compared to WKY. In conclusion, attenuated β-adrenergic vasodilatation of conduit arteries of SHR but similar β-adrenergic relaxation of resistance mesenteric arteries from WKY and SHR and their similar BP response to β-adrenergic agonists do not support major role of altered β-adrenergic vasodilatation for high BP in genetic hypertension.
Topics: Rats; Animals; Rats, Inbred SHR; Rats, Inbred WKY; Isoproterenol; Adrenergic Agents; Prostaglandin-Endoperoxide Synthases; Hypertension; Mesenteric Arteries; Adrenergic beta-Agonists; Nitric Oxide Synthase; Salmeterol Xinafoate; Endothelium, Vascular; Vascular Resistance
PubMed: 37708986
DOI: 10.1016/j.ejphar.2023.176045 -
Biomolecules Sep 2022Ractopamine (RAC) is a synthetic phenethanolamine, β-adrenergic agonist used as a feed additive to develop leanness and increase feed conversion efficiency in different... (Review)
Review
Ractopamine (RAC) is a synthetic phenethanolamine, β-adrenergic agonist used as a feed additive to develop leanness and increase feed conversion efficiency in different farm animals. While RAC has been authorized as a feed additive for pigs and cattle in a limited number of countries, a great majority of jurisdictions, including the European Union (EU), China, Russia, and Taiwan, have banned its use on safety grounds. RAC has been under long scientific and political discussion as a controversial antibiotic as a feed additive. Here, we will present significant information on RAC regarding its application, detection methods, conflicts, and legal divisions that play a major role in controversial deadlock and why this issue warrants the attention of scientists, agriculturists, environmentalists, and health advocates. In this review, we highlight the potential toxicities of RAC on aquatic animals to emphasize scientific evidence and reports on the potentially harmful effects of RAC on the aquatic environment and human health.
Topics: Humans; Swine; Cattle; Animals; Animal Feed; Dissent and Disputes; Phenethylamines; Adrenergic beta-Agonists; Anti-Bacterial Agents
PubMed: 36291550
DOI: 10.3390/biom12101342 -
Diabetologia Nov 2013We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation....
AIMS/HYPOTHESIS
We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk.
METHODS
Conscious male Sprague-Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic-hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed.
RESULTS
Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin's inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia.
CONCLUSIONS/INTERPRETATION
Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin's inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes.
Topics: Adrenergic Agonists; Animals; Ethanolamines; Formoterol Fumarate; Glucose; Hypoglycemia; Hypothalamus; Male; Rats; Rats, Sprague-Dawley
PubMed: 23933834
DOI: 10.1007/s00125-013-3009-7 -
Medicina (Kaunas, Lithuania) 2005The remarkably diverse effects of the catecholamines and similar sympathomimetic agents are directly related to an understanding of the classification and different... (Review)
Review
The remarkably diverse effects of the catecholamines and similar sympathomimetic agents are directly related to an understanding of the classification and different types of adrenoreceptors. Characteristics and physiological regulatory mechanisms of the receptor result in variable response of organ systems to catecholamines stimulation. Different adrenoreceptors regulate distinct physiological processes by controlling the synthesis or release of a variety of second messengers. The goal of this review was to turn one's attention to the below mentioned aspects. There are three known subtypes of each alpha1-, alpha2- and beta-adrenoreceptor types. Structure of the adrenoreceptors, which belong to subtypes of the same receptor type, is similar and structure of the adrenoreceptors of the separate types is very different. Genetic peculiarities of the receptors may influence liability to some diseases. Acting on the adrenoreceptors may change function of many organs and may serve for the treatment of cardiovascular, respiratory tract diseases and allergic reactions. Selective acting on the adrenoreceptors of the separate subtypes may have the different effect on the organs. Great consideration is given for that property in the development of new drugs: substitution by different chemical radicals leads to increasing selectivity for the separate subtypes of the adrenoreceptors. The prolonged use of the adrenomimetics may lead to refractoriness.
Topics: Adrenergic Agonists; Cardiovascular Diseases; Catecholamines; Humans; Hypersensitivity; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Respiratory Tract Diseases; Tissue Distribution
PubMed: 16160421
DOI: No ID Found -
The Cochrane Database of Systematic... Oct 2008Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for... (Review)
Review
BACKGROUND
Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for anaphylaxis.
OBJECTIVES
To assess the benefits and harms of adrenaline (epinephrine) in the treatment of anaphylaxis.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1966 to March 2007), EMBASE (1966 to March 2007), CINAHL (1982 to March 2007), BIOSIS (to March 2007), ISI Web of Knowledge (to March 2007) and LILACS (to March 2007). We also searched websites listing ongoing trials: http://clinicaltrials.gov/, http://www.controlledtrials.com and http://www.actr.org.au/; and contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing adrenaline with no intervention, placebo or other adrenergic agonists were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed articles for inclusion.
MAIN RESULTS
We found no studies that satisfied the inclusion criteria.
AUTHORS' CONCLUSIONS
Based on this review, we are unable to make any new recommendations on the use of adrenaline for the treatment of anaphylaxis. Although there is a need for randomized, double-blind, placebo-controlled clinical trials of high methodological quality in order to define the true extent of benefits from the administration of adrenaline in anaphylaxis, such trials are unlikely to be performed in individuals with anaphylaxis. Indeed, they might be unethical because prompt treatment with adrenaline is deemed to be critically important for survival in anaphylaxis. Also, such studies would be difficult to conduct because anaphylactic episodes usually occur without warning, often in a non-medical setting, and differ in severity both among individuals and from one episode to another in the same individual. Consequently, obtaining baseline measurements and frequent timed measurements might be difficult, or impossible, to obtain. In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular (i.m.) injection should still be regarded as first-line treatment for the management of anaphylaxis.
Topics: Adrenergic Agonists; Anaphylaxis; Epinephrine; Humans; Shock; Vasoconstrictor Agents
PubMed: 18843712
DOI: 10.1002/14651858.CD006312.pub2 -
British Journal of Pharmacology Feb 20001. This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to beta-adrenoceptor (beta-AR) stimulation. The beta 1- and beta...
1. This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to beta-adrenoceptor (beta-AR) stimulation. The beta 1- and beta 3-AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non-selective and selective beta 1/beta 3-AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, triiodothyronine (T3)-treated and thyroidectomized rats. 2. The beta 3-AR density was enhanced (72%) by T3-treatment and reduced (50%) by introduction of a hypothyroid state while beta 1-AR number remained unaffected. The beta 1- and beta 3-AR density was correlated with the specific mRNA level in all thyroid status. 3. The lipolytic responses to isoprenaline, noradrenaline (beta 1/beta 3/beta 3-AR agonists) and BRL 37344 (beta 3-AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism. 4. T3-treatment increased the maximal lipolytic response to the partial beta 3-AR (CGP 12177) and beta 1-AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy. 5. In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17 +/- 0.03 versus 0.41 +/- 0.08 mumol glycerol/10(6) adipocytes; 0.048 +/- 0.005 versus 0.114 +/- 0.006 pmol cyclic AMP min-1 mg-1) but not changed with xamoterol. 6. The changes in lipolytic responses to postreceptor-acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states. 7. Thyroid status affects lipolysis by modifying beta 3-AR density and postreceptor events without changes in the beta 1-AR functionality.
Topics: Adenylyl Cyclases; Adipose Tissue; Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blotting, Northern; Cell Membrane; Colforsin; Hyperthyroidism; Hypothyroidism; Kinetics; Lipolysis; Male; Propanolamines; RNA, Messenger; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Thyroidectomy
PubMed: 10711342
DOI: 10.1038/sj.bjp.0703008 -
Urology Journal Sep 2013To discuss the pharmacotherapeutic aspects of Mirabegron which is a first-in class novel β3 receptor agonist drug recently approved by the food and drug administration... (Review)
Review
PURPOSE
To discuss the pharmacotherapeutic aspects of Mirabegron which is a first-in class novel β3 receptor agonist drug recently approved by the food and drug administration (FDA) for the treatment of overactive bladder (OAB).
MATERIALS AND METHODS
We conducted a computerized search of the MEDLINE/PUBMED databases with the word Mirabegron, β3 receptor agonist and overactive bladder.
RESULTS
Effect of Mirabegron on β3 adrenergic receptor purportedly releases nitric oxide(NO) by an increase in intracellular Ca2+ through accumulation of cyclic adenosine monophosphate (cAMP). Along with NO which relaxes the detrusor muscle, it also releases an urothelial-derived inhibiting factor (UDIF) that inhibits contractions. It increases the bladder capacity by causing bladder relaxation during the storage phase.
CONCLUSION
Mirabegron appears to be a promising treatment in OAB patients by shifting its management from reducing detrusor over-activity to inducing relaxation. Also it lacks the troublesome side effects associated with the standard antimuscarinic management.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Humans; Muscarinic Antagonists; Thiazoles; Urinary Bladder, Overactive
PubMed: 24078498
DOI: No ID Found -
The Cochrane Database of Systematic... Aug 2012Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may cause death. Adrenaline (epinephrine) auto-injectors are recommended as the initial,... (Review)
Review
BACKGROUND
Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may cause death. Adrenaline (epinephrine) auto-injectors are recommended as the initial, potentially life-saving treatment of choice for anaphylaxis in the community, but they are not universally available and have limitations in their use.
OBJECTIVES
To assess the effectiveness of adrenaline (epinephrine) auto-injectors in relieving respiratory, cardiovascular, and other symptoms during episodes of anaphylaxis that occur in the community.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (Ovid SP) (1950 to January 2012), EMBASE (Ovid SP) (1980 to January 2012 ), CINAHL (EBSCO host) (1982 to January 2012 ), AMED (EBSCO host) (1985 to January 2012 ), LILACS, (BIREME) (1980 to January 2012 ), ISI Web of Science (1950 to January 2012 ). We adapted our search terms for other databases. We also searched websites listing on-going trials: the World Health Organization International Clinical Trials Registry Platform, the UK Clinical Research Network Study Portfolio, and the meta Register of Controlled Trials; and contacted pharmaceutical companies who manufacture adrenaline auto-injectors in an attempt to locate unpublished material.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing auto-injector administration of adrenaline with any control including no intervention, placebo, or other adrenergic agonists were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed articles for inclusion.
MAIN RESULTS
None of the 1328 studies that were identified satisfied the inclusion criteria.
AUTHORS' CONCLUSIONS
Based on this review, we cannot make any new recommendations on the effectiveness of adrenaline auto-injectors for the treatment of anaphylaxis. Although randomized, double-blind, placebo-controlled clinical trials of high methodological quality are necessary to define the true extent of benefits from the administration of adrenaline in anaphylaxis via an auto-injector, such trials are unlikely to be performed in individuals experiencing anaphylaxis because of ethical concerns associated with randomization to placebo. There is, however, a need to consider trials in which, for example, auto-injectors of different doses of adrenaline and differing devices are compared in order to provide greater clarity on the dose and device of choice. Such trials would be practically challenging to conduct. In the absence of appropriate trials, we recommend that adrenaline administration by auto-injector should still be regarded as the most effective first-line treatment for the management of anaphylaxis in the community. In countries where auto-injectors are not commonly used, it may be possible to conduct trials to compare administration of adrenaline via auto-injector with adrenaline administered by syringe and ampoule, or comparing the effectiveness of two different types of auto-injector.
Topics: Adrenergic Agonists; Anaphylaxis; Epinephrine; Humans; Injections, Intramuscular; Self Administration
PubMed: 22895980
DOI: 10.1002/14651858.CD008935.pub2 -
The Journal of Clinical Investigation Jun 1996The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a...
The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a highly selective beta 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice. Daily injection of CL (0.1 mg/kg, sc) to obese yellow KK mice for two weeks caused a significant reduction of body weight, associated with a marked decrease of white fat pad weight and hypertrophy of the interscapular BAT with a sixfold increase in UCP content. Clear signals of UCP protein and mRNA were detected by Western and Northern blot analyses in inguinal, mesenteric and retroperitoneal white fat pads, and also in gastrocnemius and quadriceps muscles, whereas no signal in saline-treated mice. The presence of UCP mRNA in muscle tissues was also confirmed by reverse transcription-PCR analysis. Weaker UCP signals were also detected in control C57BL mice treated with CL, but only in inguinal and retroperitoneal fat pads. Immunohistochemical examinations revealed that UCP stains in the white fat pads were localized on multilocular cells quite similar to typical brown adipocyte, and those in the muscle tissues on myocytes. The mitochondrial localization of UCP in myocytes was confirmed by immunoelectron microscopy. In addition to UCP protein, UCP mRNA was also detected in myocytes by in situ hybridization analysis. Thus, chronic stimulation of the beta 3-adrenergic receptor induces ectopic expression of UCP in adipose tissues conventionally considered as white fat and even in skeletal muscle, which probably contributes to the potent anti-obesity effect of the beta 3-adrenergic agonist.
Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Base Sequence; Carrier Proteins; Dioxoles; Female; Ion Channels; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Molecular Sequence Data; Muscle, Skeletal; Obesity; RNA, Messenger; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Uncoupling Protein 1
PubMed: 8675704
DOI: 10.1172/JCI118748