Effects of Natural Monoamine Oxidase Inhibitors on Anxiety-Like Behavior in Zebrafish

Abstract

Monoamine oxidases (MAO) are a valuable class of mitochondrial enzymes with a critical role in neuromodulation. In this study, we investigated the effect of natural MAO inhibitors on novel environment-induced anxiety by using the zebrafish novel tank test (NTT). Because zebrafish spend more time at the bottom of the tank when they are anxious, anxiolytic compounds increase the time zebrafish spend at the top of the tank and vice versa. Using this paradigm, we found that harmane, norharmane, and 1,2,3,4-tetrahydroisoquinoline (TIQ) induce anxiolytic-like effects in zebrafish, causing them to spend more time at the top of the test tank and less time at the bottom. 2,3,6-trimethyl-1,4-naphtoquinone (TMN) induced an interesting mix of both anxiolytic- and anxiogenic-like effects during the first and second halves of the test, respectively. TIQ was unique in having no observable effect on general movement. Similarly, a reference MAO inhibitor clorgyline—but not pargyline—increased the time spent at the top in a concentration-dependent manner. We also demonstrated that the brain bioavailability of these compounds are high based on the ex vivo bioavailability assay and in silico prediction models, which support the notion that the observed effects on anxiety-like behavior in zebrafish were most likely due to the direct effect of these compounds in the brain. This study is the first investigation to demonstrate the anxiolytic-like effects of MAO inhibitors on novel environment-induced anxiety in zebrafish.

Hepatoprotective Mechanism of Apigenin via Suppression of Oxidative Inflammatory Signaling and Apoptosis against Hepatotoxicity Induced by CCl4 in Rats

“…ALT and AST are enzymes mainly confined within the hepatocytes, although they are also found in the heart, kidney, blood cells and pancreas (Aja et al 2020) while monoamine oxidase is a mitochondrial enzyme with high activity in the brain, GIT and hepatic tissue (Jaka et al (2021). CCl 4 significantly increased the serum activities of ALT, AST and MAO compared to normal control.…”

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma

“…Norsolorinic acid [105 ] Averufin Another notable naphthoquinone, 2,3,6-trimethyl-1,4-naphthoquinone 110, was extracted and isolated from cured tobacco leaves (Nicotiana tabacum) and was found to be a competitive inhibitor of human MAO (human liver mitochondrial preparation) with Ki values of 3 and 6 μM for MAO-A and MAO-B, respectively [168]. Recent studies found using a human MAO assay that 110 inhibited MAOs with IC50 values of 1.14 and 7.14 μM for MAO-A and MAO-B, respectively [169]. The same authors evaluated the anxiolytic effects of 110 on a zebrafish model, describing that the compound induced anxiolytic and anxiogenic-like effects on the model tested [169].…”

“…Recent studies found using a human MAO assay that 110 inhibited MAOs with IC50 values of 1.14 and 7.14 μM for MAO-A and MAO-B, respectively [169]. The same authors evaluated the anxiolytic effects of 110 on a zebrafish model, describing that the compound induced anxiolytic and anxiogenic-like effects on the model tested [169]. Menadione 111, a naphthoquinone formed by metabolism from the dietary vitamin K (menaquinones), was reported as selective MAO-B inhibitor with a Ki value of 0.4 μM [170].…”

Anxiety, Insomnia, and Memory Impairment in Metabolic Syndrome Rats Are Alleviated by the Novel Functional Ingredients from Anacardium occidentale

“…The disturbance of monoamine transmitters plays an important role in mood disorders, and the suppression of monoamine oxidase (MAO) can improve mood disorders such as anxiety [ 66 , 67 , 68 ]. A recent finding demonstrated that monoamine oxidase inhibitor (MAOI) also exhibits a neuroprotective effect [ 69 ] and improves memory [ 70 , 71 ]. Obesity, one of the components of metabolic syndrome, increases MAO [ 72 , 73 , 74 ].…”