Isoliquiritigenin, a potent human monoamine oxidase inhibitor, modulates dopamine D1, D3, and vasopressin V1A receptors

Isoliquiritigenin (= 4,2′,4′-Trihydroxychalcone) (ILG) is a major constituent of the Glycyrrhizae Rhizoma that has significant neuroprotective functions. In the present study, we re-examined the potential of ILG to inhibit human monoamine oxidase (hMAO) in vitro and established its mechanism of inhibition through a kinetics study and molecular docking examination. ILG showed competitive inhibition of hMAO-A and mixed inhibition of hMAO-B with IC50 values of 0.68 and 0.33 µM, respectively, which varied slightly from the reported IC50 values. Since ILG has been reported to reduce dopaminergic neurodegeneration and psychostimulant-induced toxicity (both of which are related to dopamine and vasopressin receptors), we investigated the binding affinity and modulatory functions of ILG on dopamine and vasopressin receptors. ILG was explored as an antagonist of the D1 receptor and an agonist of the D3 and V1A receptors with good potency. An in silico docking investigation revealed that ILG can interact with active site residues at target receptors with low binding energies. These activities of ILG on hMAO and brain receptors suggest the potential role of the compound to ameliorate dopaminergic deficits, depression, anxiety, and associated symptoms in Parkinson’s disease and other neuronal disorders.

Pharmacological Modulation of Behaviour, Serotonin and Dopamine Levels in Daphnia magna Exposed to the Monoamine Oxidase Inhibitor Deprenyl

This study assessed the effects of the monoamine oxidase (MAO) inhibitor deprenyl in Daphnia magna locomotor activity. The mechanisms of action of deprenyl were also determined by studying the relationship between behaviour, MAO activity and neurotransmitter levels. Modulation of the D. magna monoamine system was accomplished by 24 h exposure to two model psychotropic pharmaceuticals with antagonistic and agonistic serotonin signalling properties: 10 mg/L of 4-chloro-DL-phenylalanine (PCPA) and 1 mg/L of deprenyl, respectively. Contrasting behavioural outcomes were observed for deprenyl and PCPA reflected in decreased basal locomotor activity and enhanced habituation for the former compound and delayed habituation for the latter one. Deprenyl exposure inhibited monoamine oxidase (MAO) activity and increased the concentrations of serotonin, dopamine and the dopamine metabolite 3-methoxytyramine in whole D. magna extracts. Our findings indicate that D. magna is a sensitive and useful nonvertebrate model for assessing the effects of short-term exposure to chemicals that alter monoamine signalling changes.

Perioperative adolescent serotonin syndrome secondary to methadone and fentanyl administration: A case report

Serotonin Syndrome (SS) is a serious toxidrome associated with significant morbidity when undiagnosed or improperly managed. We report a perioperative case of serotonin syndrome in an adolescent male on fluoxetine (selective serotonin reuptake inhibitor-SSRI) therapy secondary to an intraoperative combined opioid analgesic regiment. He received low dose methadone and fentanyl for induction for a LeFort osteotomy, the presumed trigger for his perioperative SS. This study demonstrates the essential need for anesthesiologists’ vigilance regarding identifying SS, risk factors of SS and implementation of immediate and effective management. Abbreviations: GAD: Generalized Anxiety Disorder; GPCR: G-protein Coupled Receptor; IV: Intravenous; MAOI: Monoamine Oxidase Inhibitor; MDD: Major Depressive Disorder; OR: Operating Room; PACU: Post-Anesthesia Care Unit; RAE: Right Angle Endotracheal; SERT: Serotonin Transporter; SNRI: Serotonin-Norepinephrine Reuptake Inhibitor; SS: Serotonin Syndrome; SSRI: Selective Serotonin Reuptake Inhibitor.

Pharmahuasca Reduces ROS Production and inflammatory Gene Expression in the Brain in a Model of PTSD: Exploration by RNA Sequencing

Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress and inflammation. N,N-dimethyltryptamine (DMT) is a known neuroprotective, antioxidant, anti-inflammatory, and psychoplastogen with antidepressant effects. Therefore, we tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and “pharmahuasca” (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and modulate neuroplasticity-related gene expression in a predator exposure and psychosocial stress rat model of PTSD. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), or pharmahuasca every other day for 5 days. We measured ROS production in the prefrontal cortex (PFC) and hippocampus (HC) by electron paramagnetic resonance spectroscopy (EPR) and extracted total RNA from the PFC for sequencing. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at the 5HT2AR. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. RNA sequencing implicated genes related to ROS production, inflammation, neurotransmission, and neuroplasticity. DMT, but not harmaline exhibits both affinity and efficacy at the human 5HT2AR. DMT and pharmahuasca exhibit broad effects that may facilitate the treatment of PTSD by reducing ROS production and inflammatory gene expression, and inducing neuroplasticity.

Mechanism of Delayed Convulsion in Fish: The Actions of Norepinephrine in Spinal Cord

Cranial spiking (CS) is among the most popular slaughtering methods for delaying the rigor mortis progress of fish muscles. However, it may cause a convulsion (subsequently referred to as delayed convulsion), which undermines the meat quality and taste. This study aimed to elucidate the mechanism underlying the delayed convulsion and examine its influence on ATP consumption. Ten carps, nine tilapias, ten rainbow trouts, two ayus, three greenling, thirty-five red seabreams, two striped jack and two stone flounders underwent CS around the medulla oblongata area, which induced different delayed convulsion profiles specific to each species. To investigate the norepinephrine (NE) actions related to delayed convulsion, 27 red seabreams, a representative fish species that exhibits delayed convulsion, were treated with a monoamine-depleting agent, reserpine, or with a monoamine oxidase inhibitor, pargyline, two hours before CS. Spinal cord destruction (SCD) was employed to completely prevent spinal cord functions of the fish in another group. Compared with the control group (CS only), the reserpine, pargyline, and SCD groups showed significantly inhibited delayed convulsion and ATP consumption. This suggests that delayed convulsion is the main ATP-consuming response. Our findings suggest that delayed clonic convulsion in red seabreams is associated with the rapid decrease in spinal cord NE levels, which triggered the rebound motor neuron hyperactivity.

Anti-diabetic effect of a monoamine oxidase inhibitor (tranylcypromine) in rats with poorly-controlled blood glucose levels: A potential and novel therapeutic option for diabetes

Purpose: To determine the anti-diabetic effect of a monoamine oxidase inhibitor (tranylcypromine) in sulphonyl urea-refractory rats with poorly-controlled blood glucose levels.Methods: Alloxan-induced diabetic Wistar rats were assigned to two groups (30 rats/group). One group received glibenclamide at a dose of 0.6 mg/kg, while the other group was given monoamine oxidase inhibitor (tranylcypromine) at a dose of 5 mg/day. The two groups were treated for 2 weeks. Blood samples were collected at baseline (before treatment) and at the end of treatment for determination of plasma glucose (fasting and fed), hemoglobin A1c, lipid profiles (serum total cholesterol, very-lowdensity lipoprotein, low-density lipoprotein, high-density lipoprotein and triglycerides); oxidative stress parameters (anti-oxidant enzymes), insulin levels, and some hepatic enzymes of glucose metabolism.Results: Monoamine oxidase inhibitor treatment resulted in significant decrease in the levels of blood glucose, HbA1c, and lipid levels from baseline, relative to glibenclamide (p < 0.05). Greater improvements in oxidative stress biomarkers (glutathione and superoxide dismutase), insulin levels and hepatic enzymes of glucose metabolism were observed in monoamine oxidase inhibitor group than in glibenclamide group (p < 0.05). Oxidative stress was significantly inhibited by monoamine oxidase inhibitor via increases in glutathione (GSH) level and superoxide dismutase (SOD) activity, when compared to glibenclamide (p < 0.05).Conclusion: These results suggest that monoamine oxidase inhibitor may be a better treatment option for diabetes than glibenclamide. Keywords: Diabetes, Monoamine oxidase inhibitor, Glibenclamide, Sulphonyl urea, Poorly-controlledblood glucose

A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions—post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.