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.

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

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.

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

Chronic inflammatory diseases are debilitating, affect patients’ quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer’s, and Parkinson’s; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.

POSSIBLE ANTI-DEPRESSANT EFFECT OF THE SELECTIVE COX-2 INHIBITOR MELOXICAM, ITS RELATIONSHIP WITH THE DOPAMINERGIC BRAIN SYSTEM

Inflammation is now believed to play an important role in the development of depression, and it is suggested that inflammation may be a promising target for the treatment and prevention of mood disorders. It is not surprising that various non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), are being tested for their antidepressant properties. At the same time, it is known that inhibition of COX-2 has a certain effect on the dopaminergic (DA) system. However, in the literature, there are also opposite opinions on this matter, for example, that the neuroprotective effect of NSAIDs is associated not with COX-2, but with the PI3K/Akt signaling pathway, and inhibition of COX-2 does not have a neuroprotective effect, and even negatively affects the central nervous system up to until the pathophysiology of depression aggravates. Therefore, the question of the antidepressant properties of COX-2 inhibitors remains open for further research. In addition, because of the dynamic nature of depression, it is important to ascertain whether NSAIDs may be prophylactic in the early stages of depression. Accordingly, the aim of this study was to determine the presence or absence of antidepressant potential in the selective COX-2 inhibitor meloxicam (21 days, 1 mg/kg), its possible relationship with the DA system, by tracing these effects over time. The combined use of meloxicam and haloperidol (24 days, 2.5 mg kg) in the first 7 days of the experiment did not significantly affect the level of immobility of rats in the «Forced swim test», but on days 8, 12–19, and 21 of the experiment, the level of immobility in this the group was significantly higher than in the haloperidol group. The administration of meloxicam also failed to reverse the negative effects of stress: on days 1–5, 7–12 and 15–19, there were no differences between the groups in the level of immobility, and on days 6, 13–14 and 20-21, meloxicam even increased immobility by compared with the stress group. Another evidence in favor of the depressant effect of meloxicam is the fact that it increases the level of immobility in intact rats, while the MAO inhibitor selegiline (24 days, 3 mg/kg), on the contrary, does not affect the level of immobility – the data are indistinguishable from control. Meloxicam also failed to increase locomotor activity in rats in the «Actimeter», suppressed by the combined use of haloperidol and stress. The positive effect of meloxicam was manifested only in the improvement of the task performance on the Rotarod against the background of D2-receptor blockade. Inhibition of COX-2 by meloxicam did not have the expected antidepressant effect in the «Forced swim test» and «Actimeter», but, on the contrary, led to a worsens emotional state of the animals. At the behavioral level, we were unable to obtain convincing evidence of a direct connection between the effects of meloxicam and the functioning of the DA system, although its activating effect on animal locomotion in the Rotarod test after blockade of D2-receptors with haloperidol was established.

The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.