Comparison of monoamine oxidase inhibitors in decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in PC12 cells
- The Journal of pharmacology and experimental therapeutics
- Published over 2 years ago
According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson’s disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intra-neuronal dopamine to DOPAL and may serve as a therapeutic target. The “cheese effect” - paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production has been unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All 3 drugs also increased dopamine and norepinephrine, decreased DOPA, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine auto-oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson’s disease.
Resistant hypertension (RH) treatment requires an adequate and intense therapeutic approach. However, the results are not always satisfactory despite intensive treatment. Of the different pathophysiological mechanisms involved in the pathogenesis of RH, sympathetic overstimulation and therapies that block the sympathetic system have been widely studied. These approaches, however, are invasive and expensive. Another possible approach is by transcutaneous electrical nerve stimulation (TENS), a noninvasive method that modulates activity by using low-frequency transcutaneous electrical stimulation to inhibit primary afferent pathways. Thus, the current study will evaluate the effect of applying TENS in the cervicothoracic region of subjects with RH and will seek to develop a new low-cost and readily available therapy to treat this group of hypertensive individuals.
Brown adipose tissue (BAT) plays a central role in regulating energy homeostasis, and may provide novel strategies for the treatment of human obesity. BAT-mediated thermogenesis is regulated by mitochondrial uncoupling protein 1 (UCP1) in classical brown and ectopic beige adipocytes, and is controlled by sympathetic nervous system (SNS). Previous work indicated that fish oil intake reduces fat accumulation and induces UCP1 expression in BAT; however, the detailed mechanism of this effect remains unclear. In this study, we investigated the effect of fish oil on energy expenditure and the SNS. Fish oil intake increased oxygen consumption and rectal temperature, with concomitant upregulation of UCP1 and the β3 adrenergic receptor (β3AR), two markers of beige adipocytes, in the interscapular BAT and inguinal white adipose tissue (WAT). Additionally, fish oil intake increased the elimination of urinary catecholamines and the noradrenaline (NA) turnover rate in interscapular BAT and inguinal WAT. Furthermore, the effects of fish oil on SNS-mediated energy expenditure were abolished in transient receptor potential vanilloid 1 (TRPV1) knockout mice. In conclusion, fish oil intake can induce UCP1 expression in classical brown and beige adipocytes via the SNS, thereby attenuating fat accumulation and ameliorating lipid metabolism.
[This corrects the article DOI: 10.1186/s13223-016-0110-8.].
To evaluate whether patients who experience cardiac arrest in hospital receive epinephrine (adrenaline) within the two minutes after the first defibrillation (contrary to American Heart Association guidelines) and to evaluate the association between early administration of epinephrine and outcomes in this population.
Impairments in metacognition, the ability to accurately report one’s performance, are common in patients with psychiatric disorders, where a putative neuromodulatory dysregulation provides the rationale for pharmacological interventions. Previously, we have shown how unexpected arousal modulates metacognition (Allen et al., 2016). Here, we report a double-blind, placebo-controlled, study that examined specific effects of noradrenaline and dopamine on both metacognition and perceptual decision making. Signal theoretic analysis of a global motion discrimination task with adaptive performance staircasing revealed that noradrenergic blockade (40 mg propranolol) significantly increased metacognitive performance (type-II area under the curve, AUROC2), but had no impact on perceptual decision making performance. Blockade of dopamine D2/3 receptors (400 mg amisulpride) had no effect on either metacognition or perceptual decision making. Our study is the first to show a pharmacological enhancement of metacognitive performance, in the absence of any effect on perceptual decision making. This enhancement points to a regulatory role for noradrenergic neurotransmission in perceptual metacognition.
Napping Reverses the Salivary Interleukin-6 and Urinary Norepinephrine Changes Induced by Sleep Restriction
- The Journal of clinical endocrinology and metabolism
- Published over 3 years ago
Context: Neuroendocrine and immune stresses imposed by chronic sleep restriction are known to be involved in the harmful cardiovascular effects associated with poor sleep. Objectives: Despite a well-known beneficial effect of napping on alertness, its effects on neuroendocrine stress and immune responses after sleep restriction are largely unknown. Design: A strictly controlled (sleep-wake status, light environment, caloric intake), crossover, randomized design in continuously polysomnography-monitored subjects. Setting: The study was conducted in a laboratory-based study. Participants: The subjects were 11 healthy young men. Intervention: We investigated the effects on neuroendocrine and immune biomarkers of a night of sleep restricted to 2 h followed by a day without naps or with 30 minute morning and afternoon naps, both conditions followed by an ad libitum recovery night starting at 20:00. Main Outcome Measures: Salivary interleukin-6 and urinary catecholamines were assessed throughout the daytime study periods. Results: The increase in norepinephrine values seen at the end of the afternoon after the sleep-restricted night was not present when the subjects had the opportunity to take naps. Interleukin-6 changes observed after sleep deprivation were also normalized after napping. During the recovery day in the no-nap condition, there were increased levels of afternoon epinephrine and dopamine, which was not the case in the nap condition. A recovery night after napping was associated with a reduced amount of slow-wave sleep compared to after the no-nap condition. Conclusions: Our data suggest that napping has stress-releasing and immune effects. Napping could be easily applied in real settings as a countermeasure to the detrimental health consequences of sleep debt.
The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.
Takotsubo cardiomyopathy is seen, though rarely, in anaphylaxis treated with epinephrine. Stress cardiomyopathy is most likely to occur in middle-aged women. The underlying etiology is believed to be related to catecholamine release in periods of intense stress. Catecholamines administered exogenously, and those secreted by neuroendocrine tumors (e.g., pheochromocytoma) or during anaphylaxis have been reported to cause apical ballooning syndrome, or takotsubo syndrome. However, reverse takotsubo stress cardiomyopathy is rarely seen or reported in anaphylaxis treated with epinephrine.
Management of life-threatening acute severe asthma in children and adults may require anaesthetic and intensive care. The inhaled route for drug delivery is not appropriate when only small respiratory gas volumes are shifted; the i.v. route may be associated with greater side-effects. Magnesium sulphate i.v. has a place in acute asthma management because it is a mild bronchodilator, and has a stabilizing effect on the atria which may attenuate tachycardia occurring after inhaled and i.v. salbutamol. If intubation and ventilation are required, a reduction in bronchoconstriction by any means before and during these procedures should reduce morbidity. This narrative review aims to show strengths and weakness of the evidence, present controversies, and forward opinions of the author. The review contains a practical guide to the setting up, use and efficiency of nebulizers, metered dose inhalers, and spacers (chambers). It also presents a commonsense approach to the management of severe asthmatics in whom delay in bronchodilatation would cause clinical deterioration. When self-inhaled agents have had no effect, i.v. drugs may help avoid intubation and ventilation. The review includes suggestions for the use of inhaled anaesthetics, anaesthetic induction, and brief notes on subsequent ventilation of the lungs.