A complementary and alternative natural antidepressant therapy with emphasis on their mechanisms of action

Medicinal plants can exert antidepressant activity by many mechanisms included neutralization of various stress mediators (regulate the activity of the hypothalamic- pituitary- adrenal axis and reduce CRF, and ACTH and corticosterone) [5], interaction with serotonergic systems (5-HT3, 5HT2A, 5-HT1A), noradrenergic (α1 and α2 receptors) and dopaminergic (D1 and D2) receptors [6],restoring monoamine transmitters and their receptors to normal limits in certain regions of the cortex, in addition to reducing of oxidative stress and amelioration of inflammatory mediators. The current review discussed the antidepressant activity of medicinal plants, with emphasis on their mechanisms of action.

The Use of Dexmedetomidine on Pediatrics Undergoing MRI Examinations

Dexmedetomidine, an α2 adrenergic agonist, has been commonly used as an off-label anesthetic adjuvant in various procedures and age groups. Lately, dexmedetomidine is increasingly preferred as sedation for pediatric patients undergoing MRI, which requires the patient to remain still in a deep sedation without disturbing airway patency. Dexmedetomidine administration via intranasal or buccal route is preferred for pediatric patients. Dexmedetomidine does not undergo significant pharmacokinetic changes when used in conjunction with other anesthetics, and has a good safety profile. It is 8-10 times more selective against α2 receptors than clonidine and produces sedation, analgesia, vasodilation, and bradycardia without significant airway and respiratory depression risk. Unlike other anesthetic agents, dexmedetomidine does not have any negative effect on brain development. Compared with propofol, dexmedetomidine has a longer onset and duration of action. Thus, dexmedetomidine can be used as the sole sedating agent in infants and children undergoing MRI procedures, with good sedation results and minimal side effects. However, correct dosing is very important given the side effects of bradycardia and hypotension that can occur with its use.

Glucose Intolerance on Phaeochromocytoma and Paraganglioma—The Current Understanding and Clinical Perspectives

Half of the patients with phaeochromocytoma have glucose intolerance which could be life-threatening as well as causing postoperative hypoglycemia. Glucose intolerance is due to impaired insulin secretion and/or increased insulin resistance. Impaired insulin secretion is caused by stimulating adrenergic α2 receptors of pancreatic β-cells and increased insulin resistance is caused by stimulating adrenergic α1 and β3 receptors in adipocytes, α1 and β2 receptors of pancreatic α-cells and skeletal muscle. Furthermore, different affinities to respective adrenergic receptors exist between epinephrine and norepinephrine. Clinical studies revealed patients with phaeochromocytoma had impaired insulin secretion as well as increased insulin resistance. Furthermore, excess of epinephrine could affect glucose intolerance mainly by impaired insulin secretion and excess of norepinephrine could affect glucose intolerance mainly by increased insulin resistance. Glucose intolerance on paraganglioma could be caused by increased insulin resistance mainly considering paraganglioma produces more norepinephrine than epinephrine. To conclude, the difference of actions between excess of epinephrine and norepinephrine could lead to improve understanding and management of glucose intolerance on phaeochromocytoma.

Effects of dexmedetomidine on porcine pulmonary artery vascular smooth muscle

Background: The α2-receptor agonists, dexmedetomidine (Dex) have been shown to produce sedative and analgesic effects not only with systemic administration but also when administered in the extradural space and around peripheral nerves. However, the effects and mechanism of action of Dex on pulmonary arteries have not been determined. This study therefore aimed to investigate the effect of Dex on pulmonary arterial vascular smooth muscle by evaluating changes in isometric contraction tension. We then attempted to determine the effects of Dex on depolarization stimulation and receptor stimulation. Methods: Endothelium-denuded porcine pulmonary arteries were sliced into 2- to 3-mm rings. We then exposed them to various substances at various concentrations under different conditions of baseline stimulation (with KCl, adrenaline, caffeine, or histamine) and of the α2-receptor stimulant or antagonists, or α1-receptor antagonist (with imidazoline, yohimbine, rauwolscine, or prazosin), and different conditions of Ca2+ depletion of the intracellular reservoir or extracellular stores, measuring the changes in isometric contraction tension with each addition or change in conditions. The concentration–response relation was determined at Dex concentrations of 10−10, 10−9, 10−8, 10−7, 10−6, 5×10−6, and 10−5 M and for other experiments at 5×10-6 M. Results: Dex enhanced the contraction induced by high KCl stimulation, with the increases reaching significance at Dex concentrations of ≥5×10-6 M. The Dex-induced enhancement of contraction induced by high KCl was completely suppressed by yohimbine and rauwolscine, which are α2-receptor antagonists, but not by prazosin. Dex, imidazoline, yohimbine and rauwolscine reduced the increases in contraction tension induced by the receptor stimulant adrenaline. Dex suppressed the adrenaline-induced increases in contraction tension after depletion of Ca2+ reservoir. In the absence of extracellular Ca2+, Dex suppressed the adrenaline- and histamine-induced increases, and did not affect caffeine-induced increases in contraction tension. Conclusions: Dex-enhanced high KCl-induced contraction was mediated by α2-receptors. Adrenaline-induced contraction was suppressed by the α2-receptor stimulant Dex and α2-receptor antagonists yohimbine and rauwolscine, suggesting that the effect of Dex on adrenaline-induced contraction is attributable to its α2-receptor-blocking action. Dex inhibited receptor-activated Ca2+ channels (RACCs) and phosphatidylinositol-1,4,5-triphosphate-induced Ca2+ release (IICR) but not Ca2+-induced Ca2+ release (CICR).

Effects of Diazepam on Low-Frequency and High-Frequency Electrocortical γ-Power Mediated by α1- and α2-GABAA Receptors

Patterns of spontaneous electric activity in the cerebral cortex change upon administration of benzodiazepines. Here we are testing the hypothesis that the prototypical benzodiazepine, diazepam, affects spectral power density in the low (20–50 Hz) and high (50–90 Hz) γ-band by targeting GABAA receptors harboring α1- and α2-subunits. Local field potentials (LFPs) and action potentials were recorded in the barrel cortex of wild type mice and two mutant strains in which the drug exclusively acted via GABAA receptors containing either α1- (DZα1-mice) or α2-subunits (DZα2-mice). In wild type mice, diazepam enhanced low γ-power. This effect was also evident in DZα2-mice, while diazepam decreased low γ-power in DZα1-mice. Diazepam increased correlated local LFP-activity in wild type animals and DZα2- but not in DZα1-mice. In all genotypes, spectral power density in the high γ-range and multi-unit action potential activity declined upon diazepam administration. We conclude that diazepam modifies low γ-power in opposing ways via α1- and α2-GABAA receptors. The drug’s boosting effect involves α2-receptors and an increase in local intra-cortical synchrony. Furthermore, it is important to make a distinction between high- and low γ-power when evaluating the effects of drugs that target GABAA receptors.

Role of the Anesthetic Determine the Clonidine Effects Mediated by RVLM/-α2-Adrenoceptors on Blood Pressure and Heart Rate in Rats

To examine the hypothesis of a role for α2-adrenoceptors in mediating the mechanism of urethane hypotensive effect whether it's peripheral or central, Wistar rats were anesthetized with urethane or (for comparison) with halothane, to study the influence of urethane that govern the mechanism of central and peripheral α2-adrenoceptors action, on basal BP & HR, and the rise in blood pressure (BP) to the stimulation of caudal pressor area (CPA), when these receptors were either centrally activated by bilateral rostral ventrolateral medulla (RVLM) microinjection of clonidine (30nM), and blockade with any of the clonidine antagonists, yohimbine (500pmol/50nl), and idazoxane (270nM) or yohimbine+idazoxane, or when peripherally activated (of urethane anesthetized rats) by i.v. clonidine (100nmol/kg), which also blockade with idazoxane or yohimbine+idazoxane. The results indicated presence of no anesthetic differences in a partial involvement of α2-receptors-RVLM, vs. a complete involvement of I(1)-imidazole receptors in mediating the hypotensive effects of clonidine. It also indicates α2-/I(1)-receptors synergism in raising the urethane lowering of baseline of SBP to the levels of control or halothane group. In conclusion, the result suggests involvement both of the central and the peripheral α2-adrenoceptors in mediating urethane hypotensive effects.

Ancient coexistence of norepinephrine, tyramine, and octopamine signaling in bilaterians

Norepinephrine/noradrenaline is a neurotransmitter implicated in arousal and other aspects of vertebrate behavior and physiology. In invertebrates, adrenergic signaling is considered absent and analogous functions are performed by the biogenic amines octopamine and its precursor tyramine. These chemically similar transmitters signal by related families of GPCR in vertebrates and invertebrates, suggesting that octopamine/tyramine are the invertebrate equivalents of vertebrate norepinephrine. However, the evolutionary relationships and origin of these transmitter systems remain unclear. Using phylogenetic analysis and receptor pharmacology, here we establish that norepinephrine, octopamine, and tyramine receptors coexist in some marine invertebrates. In the protostomes Platynereis dumerilii (an annelid) and Priapulus caudatus (a priapulid) we identified and pharmacologically characterized adrenergic α1 and α2 receptors that coexist with octopamine α, octopamine β, tyramine type 1, and tyramine 2 receptors. These receptors represent the first examples of adrenergic receptors in protostomes. In the deuterostome Saccoglossus kowalewskii (a hemichordate), we identified and characterized octopamine α, octopamine β, tyramine type 1, and tyramine 2 receptors, representing the first example of these receptors in deuterostomes. S. kowalewskii also has adrenergic α1 and α2 receptors, indicating that all three signaling systems coexist in this animal. In phylogenetic analysis, we also identified adrenergic and tyramine receptor orthologs in xenacoelomorphs. Our results clarify the history of monoamine signaling in bilaterians. Since all six receptor families (two each for octopamine and tyramine and three for norepinephrine) can be found in representatives of the two major clades of Bilateria, the protostomes and the deuterostomes, all six receptors coexisted in the protostome-deuterostome last common ancestor. Adrenergic receptors were lost from most insects and nematodes and tyramine and octopamine receptors were lost from most deuterostomes. This complex scenario of differential losses cautions that octopamine signaling in protostomes is not a good model for adrenergic signaling in deuterostomes, and that the studies of marine animals where all three transmitter systems coexist will be needed for a better understanding of the origin and ancestral functions of these transmitters.