MAO Activity Research Articles

Galactose Impairs Motor Performance and Cerebellar Signaling in Young Male Wistar Rats.

Galactosemias are a group of inborn errors of galactose metabolism that causes different motor symptoms such as ataxia, tremor, and fine motor dysfunction. The objective was to investigate the cerebellar damage caused by an acute galactose administration. Thirty-day-old male and female Wistar rats were used. Animals were randomized into the following groups: I) galactose group, receiving a single subcutaneous administration of galactose; II) control group, receiving the vehicle solution under the same conditions. One, 3 or 24h after administration, the animals were evaluated in the Rotarod test. A lower motor performance was observed in male rats 3h after a galactose administration. This effect was not seen in females or with galactose exposure for 1 or 24h. The activities of acetylcholinesterase and choline acetyltransferase were found unaltered in the cerebellum of males 3h after galactose injection. We also found lower TH levels in cerebellar hemispheres and higher TH levels in cerebellar vermis 3h after galactose administration in male rats, without differences in MAO-A or MAO-B activities. Galactose administration resulted in lower p-CREB(Ser133) and GAD67 levels in cerebellar hemispheres, without altering these parameters in cerebellar vermis of male rats. Finally, a decrease in TrkB-FL immunocontent (but not of TrkB-T levels) was observed in male cerebellar hemispheres. The absence of neurochemical alterations 1h or 24h after galactose administration indicates a transient effect for this hexose. The signs and symptoms of galactosemic patients underscore the need to study galactose effects in males and females and in various brain areas. Our findings enhance the understanding of therapeutic mechanisms of catecholaminergic drugs, which are proposed as a potential therapy for galactosemia.

Theranostic Near-Infrared Monoamine Oxidase Inhibitor (NMI) Protein Binding Interactions with MAOA and Albumin.

The protein binding interactions of near-infrared monoamine oxidase inhibitor (NMI) are reported here. NMI-bound proteins were examined by fluorescent SDS-PAGE and mass spectrometry using tumor tissues from brain and colon cancer mouse models. This study shows protein interactions with NMI, a chemical conjugate of MAOA inhibitor clorgyline and tumor-seeking dye, MHI-148. NMI fluorescence in MAOA knock-out (KO) mice was significantly lower compared to WT mice, including whole animal, organs, and tissue lysates which indicated that NMI binds to MAOA. Pure recombinant MAOA protein was detectable as a single fluorescent band that migrated at ~ 65kD. NMI inhibited MAOA activity (IC50 1-5µM). In a glioma mouse model, NMI targeted specifically to tumor with high contrast to adjacent normal brain, shown by a 65 kD protein band. Recent studies demonstrated heptamethine cyanine dyes (e.g., MHI-148) interact with serum albumin, contributing to tumor uptake and cancer cell internalization. Our study shows NMI binds to albumin but highly prefers MAOA, providing a plausible mechanism for systemic drug delivery via serum albumin to the tumor target and subsequent MAOA inhibition. Further studies in a colon cancer mouse model found the ~ 65 kD SDS-PAGE band, bound to NMI, contained both MAOA and albumin proteins by mass spectrometry. NMI was shown to interact with MAOA and the blood carrier protein, albumin. This study provides insights for drug delivery and protein target specificity of NMI to image and treat cancer.

Acute Toxicity and Neuroprotective Effect of "RJ6601", a Newly Formulated Instant Soup, in Geriatric Rats.

Given its antioxidant effects and central nervous system benefits, we hypothesized that RJ6601 should improve neurodegeneration in the hippocampus, a region critical for cognition and the maintenance of quality of life (QoL). To assure its safety, a single fixed dose of 2000 mg/kg BW was administered to female Wistar rats (250-450 g, 18 months old) to test the acute toxicity of RJ6601. No mortality and toxicity signs were observed. To prove that RJ6601 can protect against age-related neurodegeneration, RJ6601 at doses of 200 and 400 mg/kg BW was administered to the female Wistar rats once daily for 4 weeks. At the end of the study period, assessments were conducted to evaluate the neuron density; MDA levels; and activities of SOD, CAT, GSH-Px, AChE, total MAO, MAO-A, and MAO-B in the hippocampus. Our results reveal increased neuron density, SOD, CAT, and GSH-Px but decreased MDA, AChE, total MAO, MAO-A, and MAO-B in the hippocampi of female Wistar rats subjected to RJ6601 treatment at both doses used in this study. Therefore, RJ6601 is considered to have low toxicity and may improve neurodegeneration as well as cholinergic and monoaminergic dysfunctions. Subchronic toxicity studies and clinical trials are essential to confirm the safety of RJ6601 consumption and its health benefits.

Intestinal monoamine oxidase activity in premature and full-term infants with surgical pathology

Advances in pediatric surgery, intensive care, and anesthesiology have significantly improved the outcomes of surgical treatment of full-term and premature infants with intestinal malformations and necrotizing enterocolitis (NEC). The main challenges in treating children of this complex group today lie in improving diagnostics, choosing treatment tactics, and ensuring the postoperative period. Monoamine oxidase (MAO) is a mitochondrial enzyme that catalyzes oxidative deamination of biogenic and xenobiotic monoamines, including those in intestinal wall cells and tissues. It can be a prognostic and diagnostic marker of the effectiveness and rate of intestinal recovery in the postoperative period, and also serve as a point of application for pharmacological correction. The aim of the study is to determine the activity of intestinal MAO in children of the first year of life with surgical pathology. Material and methods. The study included 24 patients with colon and small intestine pathologies, aged from 1 day to 3 months, who were treated at the Chelyabinsk Regional Children’s Clinical Hospital from October 2022 to May 2024. MAO-A and MAO-B activity was studied by spectrophotometry in intestinal homogenates obtained at the proximal resection margin. Results and discussion. Intestinal samples obtained from patients with diseases accompanied by pronounced inflammatory changes (NEC stage IIIA–IIIB, enterostomy closure after NEC III, intestinal neuronal dysplasia (IND), Hirschsprung’s disease) showed a significant decrease in the activity of the MAO-A isoform. A decrease in MAO-B activity was demonstrated in intestinal wall samples obtained from children with confirmed diagnoses of Hirschsprung’s disease and intestinal neuronal dysplasia, as well as in premature infants with surgical stages of NEC. The highest activity of both enzyme isoforms was found in sigmoid colon samples without pathological changes in patients with anal and rectum atresia.

Ashwagandha (Withania somnifera (L.) dunal) root extract containing withanolide a alleviates depression-like behavior in mice by enhancing the brain-derived neurotrophic factor pathway under unexpected chronic mild stress.

Ashwagandha (Withania somnifera (L.) Dunal) root or whole-plant extracts are used to treat anxiety, insomnia, and other nervous system disturbances. We evaluated the neuroprotective and antidepressant effects of ashwagandha root extract (ARE) on corticosterone-exposed HT-22cells and unpredictable chronic mild stress (UCMS)-challenged mice. The neuroprotective properties of ARE containing withanolide A were assessed in HT-22cells subjected to corticosterone-induced oxidative stress. Additionally, the effects of ARE on depression-like behavior, stress-related hormones, and inflammatory cytokine levels were evaluated in a mouse model of UCMS. In HT-22cells, ARE (100 and 200μg/mL) and its constituent, withanolide A (1.56 and 3.12μg/mL), mitigated corticosterone-induced increases in MAO activity, ROS, and MDA levels. Treatment also reversed corticosterone-induced reductions in BDNF, TrkB, p-AKT, p-ERK, and p-CREB and normalized Nrf2 and Keap1 levels, thereby elevating HO-1 expression. In UCMS mice, ARE improved behavioral outcomes, increased sucrose preference, and reduced immobility in the forced swimming test while enhancing activity in the open field test and elevated plus maze. ARE decreased the levels of stress hormones (corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone) and increased the levels of neurotransmitters (L-DOPA, 5-HTP, and serotonin). Histological analysis revealed that ARE reduced hippocampal cell loss. Additionally, ARE (60 and 100mg/kg) restored decreased levels of p-AKT, p-ERK, and p-CREB and lowered inflammation-related proteins (Cox2, iNOS, IL-6, IL-1β, TNF-α). These results indicate that ARE containing withanolide A exhibits notable neuroprotective and antidepressant properties.

Chalcogen dihydrobenzofuran compounds as potential neuroprotective agents: an in vitro and in silico biological investigation.

Oxidative stress arises from an imbalance between reactive species (RS) production and the antioxidant defense, increasing the brain susceptibility to neurodegenerative and psychiatric diseases. Besides, changes in the expression or activity of neurotransmitter metabolism enzymes, such as monoamine oxidases (MAO), are also associated with mental disorders, including depression. Considering this, antioxidant and MAO-A activity inhibitory potential of six 2,3-chalcogenodihydrobenzofurans (2,3-DHBF) was investigated through in vitro and in silico tests. Compounds 1 to 5 incorporate sulfur (S) as chalcogen, whereas compound 6 integrates tellurium (Te). A screening (compounds 1-6) of cerebral MAO-A activity showed inhibitory activity for the compounds 2, 4, 5, and 6. Among sulfur compounds, compound 2 demonstrated superior scores in docking studies, yielding a value of - 9.9 kcal/mol. Selected for concentration-response curves, compounds 2 (with S) and 6 (with Te) inhibited MAO-A at concentrations equal to or higher than 25 μM. In a redox screening test, only compound 6 showed antioxidant effects. Concentration-response curves indicated that compound 6 reduced lipid peroxidation and protein carbonylation levels in mouse brain tissue (≥ 0.5 μM), as well as reduced RS levels (≥ 1 μM). Furthermore, the compound 6 (≥ 5 μM) was effective in reducing the ferric ion (FRAP). In radical scavenging tests such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), compound 6 showed significant results in concentrations from 50 μM and mimicked the enzyme glutathione S-transferase (GST) at 100 μM. In summary, this study demonstrated the cerebral antioxidant and/or MAO-A inhibition properties of 2,3-DHBF, presenting potential as neuroprotective candidates.

Key Enzymes of Serotonergic System Tryptophan Hydroxylase 2 and Monoamine Oxidase A in the Brain of Rats Selectively Bred For Reaction Toward Humans: Effects of Benzopentathiepin TC-2153

In the Institute of cytology and genetics (Novosibirsk) for over 85 generations takes place a selection of grey rats for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model to study fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects serotonergic system – an important regulator of aggression. The aim of this study was to investigate the TC-2153 effect on key serotonergic system enzymes – tryptophan hydroxylaze 2 (TPH2) and monoamine oxydase A (MAOA) – in the brain of aggressive and tame rats. TC-2153 (10 or 20 mg/kg) or vehicle were administered once i.p. to male aggressive and tame rats. TPH2 and MAOA enzymatic activity, mRNA and protein levels were assessed. Selection for high aggression level resulted in elevated Tph2 mRNA levels in the midbrain, TPH2 protein in hippocampus and TPH2 and MAOA proteins in hypothalamus. MAO activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. Single TC-2153 administration decreased TPH2 and MAO activity in hypothalamus and midbrain respectively. The drug acted upon MAOA protein levels in hypothalamus: elevated that of aggressive rats and decreased in the tame ones. Thus, this study shows profound differences in the expression and activity of the key serotonergic system enzymes in the brain of rats selectively bred for highly aggressive behavior toward humans and its absence, and effects of benzopentathiepin TC-2153 on these enzymes may point to the mechanisms of its antiaggressive action.

Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration.

Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene. The isoform-specific transcription organization regulates expression and function of MAO-A in response to cellular signaling pathways and environmental factors. MAO-A shows distinct properties and functions: isoform-specified polymorphisms, localization in catecholamine neurons, expression during early embryonic stage, regulation of brain architecture development and mediation of death and survival of neuronal cells. MAO-A is more flexible to genetic and environmental changes than MAO-B. Defective MAO-A expression impairs embryonic brain development and causes adult abnormal mood and behavior, as shown by human male cases with MAO-A deletion. This paper presents the regulation of brain MAO-A expression epigenetically by interaction between genetic and environmental factors. Association of aberrant MAO-A expression and activity with aggression, asocial behaviors, depressive disorders, and neurodegenerative diseases is discussed. Novel therapeutic strategy for psychiatric diseases by intervention to the regulation of MAO-A expression and activity is proposed.

Corema album Berry Juice as a Protective Agent Against Neurodegeneration.

Background/Objectives: Corema album berries are edible fruits from the Iberian Atlantic coast, characterized by a rich polyphenolic composition, which endows their juice with potential protective effects against neurodegeneration. This study aimed to evaluate the potential of the relatively lesser-known C. album berries as a novel neuroprotective agent against neurodegenerative diseases. Methods: The phenolic compounds of the juice were characterized using UHPLC-HRMS (Orbitrap). The SH-SY5Y neuroblastoma line was used to determine the preventive effect of the juice against H2O2-induced oxidative stress. Furthermore, neuronal cells were differentiated into dopaminergic and cholinergic lines and exposed to 6-hydroxydopamine and okadaic acid, respectively, to simulate in vitro models of Parkinson's disease and Alzheimer's disease. The ability of the juice to enhance neuronal viability under toxic conditions was examined. Additionally, its inhibitory effects on neuroprotective-related enzymes, including MAO-A and MAO-B, were assessed in vitro. Results: Phytochemical characterization reveals that 5-O-caffeoylquinic acid constitutes 80% of the total phenolic compounds. Higher concentrations of the juice effectively protected both differentiated and undifferentiated SH-SY5Y cells from H2O2-induced oxidative damage, reducing oxidative stress by approximately 20% and suggesting a dose-dependent mechanism. Moreover, the presence of the juice significantly enhanced the viability of dopaminergic and cholinergic cells exposed to neurotoxic agents. In vitro, the juice inhibited the activity of MAO-A (IC50 = 87.21 µg/mL) and MAO-B (IC50 = 56.50 µg/mL). Conclusions: While these findings highlight C. album berries as a promising neuroprotective agent, further research is required to elucidate its neuroprotective mechanisms in cell and animal models and, ultimately, in human trials.

A Preliminary Antidepressant Assessment of a Novel Piperoyl Amide (Y3) Isolated and Elucidated from Piper nigrum Drupes Extract, Justifying Interaction Over MAO-A enzyme: An in vivo, in vitro and Molecular Docking Approach

This research aims to confirm the preliminary antidepressant activity of a newly discovered piperoyl amide (Y3) obtained from the extract of Piper nigrum (P. nigrum) drupes, through the inhibition of MAO-A enzyme. Column chromatography was employed for isolation and purification of Novel piperoyl-alkyl amide (Y3) which was eluted in a solvent mixture of Chloroform-Methanol (97:3). Structure elucidation was performed by implying spectroscopic techniques. Invitro in-comparison MAO activity assessment was performed between Y3 and piperine further confirmed by Molecular docking via Auto Dock Tools 1.5.6, Vina, and PyMOL. Invivo antidepressant activity was evaluated by the Despair Test in albino mice. Novel piperoyl-alkyl amide (Y3) was isolated and purified by column chromatography and elucidated spectroscopically. The antidepressant activity of Y3 at 10 and 20 mg/kg doses shown a significant decrease in immobility-time (IT) in contrast to stressed-control group at 107.0±7.6 sec (P<0.05) and 96.0±7.6 sec (P<0.01), respectively. Y3 shown a decent MAO-A inhibitory activity but lower than piperine showing IC50=20.24 µM, Vmax=1.375±0.3 nM/min/mg, Km=1.379×10-16 µM with a stronger interaction and better affinity (-12.6 kcal/mol) towards the active-site of MAO-A. Y3 was isolated and elucidated as (12E,14E)-15-(benzo[d] [1,3] dioxol-5-yl)-N-ethylpentadeca-12,14-dienamide. It proved a good antidepressant at 10 and 20 mg/kg doses. Molecular docking over MAO-A and QSAR studies depicted a better affinity score of Y3 than Piperine. Keywords: Piperoyl amide, Structure elucidation, antidepressant activity, molecular modeling, Piperine

Evaluation of Anti-Depressant Potential of Standardized Hydroethanolic Extract of S. barbata D. Don Using Chronic Unpredictable Mild Stress Model

Background: S. barbata D. Don is a Chinese herb, that belongs to the family Lami-aceae. It has established traditional use in ethnomedicine for treating various ailments, includ-ing mood disorders and sleep disorders, which led to growing interest in exploring its neuro-logical potential, particularly as a potential anti-depressant agent. Aims: This study explores the anti-depressant potential of the HSBE utilizing a Chronic Un-predictable Mild Stress-induced depression model in mice. Additionally, the research aims to elucidate the underlying mechanisms of action. Methods: Swiss albino mice were subjected to a 3-week CUMS paradigm and subsequently administered HSBE at doses of 200 and 400 mg/kg via oral administration. The behavioral alterations were evaluated using the FST, TST, OFT, and SPT. Brain levels of serotonin, dopa-mine, and nor-epinephrine were estimated in different brain regions (cortex, hippocampus, and hypothalamus) to uncover the molecular mechanism. Additionally, assays for monoamine oxi-dase-A, monoamine oxidase-B, and antioxidant enzyme activities were conducted. Plasma ni-trite and corticosterone levels were also measured to get further insight into potential mecha-nisms underlying the anti-depressant effects of HSBE. Results: HSBE significantly ameliorated depressive-like behavior induced by CUMS para-digm, as evidenced by reduced immobility in FST and TST, increased locomotor activity in OFT, and improved sucrose preference in SPT. Neurochemical analysis revealed a significant increase in serotonin, dopamine, and norepinephrine levels in the cortex, hippocampus, and hypothalamus of HSBE-treated mice, implying a potential regulation of monoaminergic neuro-transmitter levels. Moreover, biochemical analyses demonstrated a significant inhibition of both MAO-A and MAO-B activity, contributing to the increase of the brain levels of neuro-transmitters. The administration of HSBE also led to a significant enhancement of antioxidant enzyme activities and reduced brain lipid peroxidation, indicating a pronounced antioxidant effect of HSBE. Furthermore, decreased plasma nitrite and corticosterone levels provided ad-ditional insights into HSBE's potential multi-targeted anti-depressant mechanism. Conclusion: This study indicates that HSBE exhibits robust anti-depressant properties, sup-ported by behavioral, neurochemical, and biochemical alterations. These findings underscore the therapeutic promise of HSBE as a natural intervention for depressive disorders, warranting further clinical exploration.

Intermittent access to sugary drinks associated with fasting induces overeating and depressive-like behavior in female C57BL/6J mice

Binge eating disorder is the most prevalent eating disorder, affecting both sexes but more commonly found in women. Given the frequent co-occurrence of psychiatric disorders, this study aimed to establish a standardized experimental intermittent protocol to investigate overeating associated with depression. A 10-day protocol induced uncontrolled eating behavior in C57BL/6J female mice. The first experiment included the following groups: naive group (chow ad libitum), control group (chow and sucrose solution ad libitum), and fasting groups (16 and 20 h) exposed to an intermittent sucrose solution (10 %) and chow regimen. Subsequently, the feeding test, open field test, elevated plus maze test, tail suspension test, and light/dark conflict test were conducted. Furthermore, monoamine oxidase (MAO) A and B activities in brain structures and plasma corticosterone levels were assessed. Food overconsumption and depressive-like behavior were observed in both sucrose fasting groups, while risk-taking behaviors were specifically observed in the 20-hour fasting sucrose group. While both fasting sucrose groups caused reduced hippocampal MAO-A activity, only the F20 sucrose group inhibited MAO-B in the cortex and hypothalamus. Moreover, both fasting sucrose groups exhibited elevated corticosterone levels. In a separate design (Experiment 2), groups with 16 and 20 h of fasting alone (without sucrose) did not show the same behavioral results as the intermittent fasting sucrose groups, thus avoiding fasting bias. Based on these results, the 20-hour sucrose fasting group was chosen as the ideal protocol for mimicking overeating behavior associated with depression to investigate future therapeutic approaches for this comorbidity.

Unraveling the Liver-Brain Axis: Resveratrol's Modulation of Key Enzymes in Stress-Related Anxiety.

Stress-related anxiety disorders and anxiety-like behavior in post-traumatic stress disorder (PTSD) are associated with altered neurocircuitry pathways, neurotransmitter systems, and the activities of monoamine and glucocorticoid-metabolizing enzymes. Resveratrol, a natural polyphenol, is recognized for its antioxidant, anti-inflammatory, and antipsychiatric properties. Previous studies suggest that resveratrol reduces anxiety-like behavior in animal PTSD models by downregulating key enzymes such as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and monoamine oxidases (MAOs). However, the underlying mechanisms remain unclear. In this study, we explored the efficacy of resveratrol in treating stress-induced anxiety using a chronic predator stress model in rats. Resveratrol was administered intraperitoneally at 100 mg/kg following a 10-day stress exposure, and anxiety behavior was assessed with an elevated plus maze. Our results indicated that stress-related anxiety correlated with increased activities of brain MAO-A, MAO-B, and hepatic 11β-HSD-1, alongside elevated oxidative stress markers in the brain and liver. Resveratrol treatment improved anxiety behavior and decreased enzyme activities, oxidative stress, and hepatic damage. We demonstrate that resveratrol exerts antianxiogenic effects by modulating glucocorticoid and monoamine metabolism in the brain and liver. These findings suggest resveratrol's potential as a therapeutic agent for anxiety disorders, warranting further clinical investigation.

Chemical Profile and Potential Application of Agri-food Waste Products for Counteracting Diabetes Induced Neuropathy in Rats.

This study aimed to prepare defatted ethanol extract of Abelmoschus esculentus leaves, Morus nigra leaves and Punica granatum peel, to identify the chemical composition of these extracts and to explore their efficacy in counteracting diabetic neuropathy. LC-ESI-MS spectrometry was the hyphenated tool for component identification of these extracts. Behavioral, biochemical, and histopathological investigations were carried out after treatments of diabetic rats. The phenolic contents in the extracts are 16.38, 34.75 and 40.57 mg GAE/g extract regarding A. esculentus leaves, M. nigra leaves and P. granatum peel respectively. Chemodiversity of the phenolic contents was observed from the LC/Mass, where A. esculentus extract contained isoflavonoids and flavanones, M. nigra extract consisted of benzofurans, prenylated flavonoids, stilbenes, and xanthones, and P. granatum extract was rich in ellagitanins, condensed tannins, and anthocyanins. The extracts normalize of blood glucose levels, enhance the explorative behavior of the rats and their response time to thermal pain, restore the oxidant/antioxidant balance, attenuate inflammation, augment brain monoamines levels and modulate MAO-A and Ache enzyme activity. Furthermore, they recovered brain histopathological alterations. Conclusively, this study offers experimental evidence for the neuroprotective impact of studied defatted ethanol extracts against diabetic neuropathy via their hypoglycemic effect, antioxidant activity, and anti-inflammatory potential.

Effects of association between resveratrol and ketamine on behavioral and biochemical analysis in mice.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.

Depression-reminiscent Behavior Induced by Chronic Unpredictable Mild Stress Paradigm in Mice Substantially Abrogated by Diosmin

Background: Diosmin has already been described and documented to be neuroprotective, antioxidant and anti-inflammatory. It may possess or hold depressionalleviating activity. Therefore, the purpose of the current research protocol is to investigate the depression-relieving proficiency of diosmin in stressed and unstressed mice. Methods: Male mice (Swiss albino) were imperiled to an unpredictable chronic stress paradigm every day for three sequential weeks, and depression-resembling behavioral despair was induced. Imipramine 15 mg/kg and diosmin (25, 50 and 100 mg/kg) were dispensed for 21 successive days to discrete groups of stressed and unstressed mice. Results: Both diosmin (100 mg/kg) and 15 mg/kg imipramine administration for 3 consecutive weeks substantially or significantly diminished the immobility period of mice imperiled to stress in comparison to stressed mice gauzed with the vehicle. Diosmin (25, 50 and 100 mg/kg) and imipramine considerably reinstated the diminished sucrose proclivity (sucrose preference percentage; %) in stressed mice, demonstrating their considerable or substantial depression-relieving effects. The locomotor activities of mice were not considerably altered by these drugs. Antidepressant-like activity of diosmin for immobility periods and preference for sucrose was observed to be analogous to imipramine. Diosmin (100 mg/kg) and imipramine substantially quashed CUMS- persuaded escalation of plasma corticosterone and nitrite levels, malondialdehyde levels and MAO-A activity in the brain of stressed mice. Both drugs also substantially reversed CUMS-prompted reduction in catalase activity and brain glutathione levels. Conclusion: Accordingly, diosmin revealed significant anti-depressive activity in mice imperiled to chronic mild unpredictable stress paradigm conceivably via mitigation of nitrosative and oxidative stress, reticence of brain MAO-A action, and sink drop of plasma corticosterone degrees.

Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 µM), followed by IB3 (IC50 = 0.019 µM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 µM), followed by IB4 (IC50 = 1.87 µM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B. Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

Anxiolytic, Antidepression, and Memory-Enhancing Effects of the Novel Instant Soup RJ6601 in the Middle-Aged of Female Rats.

Due to the health benefits of polyphenols and dietary fiber in combating mental disorders, we hypothesized that a polyphenol- and dietary fiber-enriched soup (RJ6601) would improve mental wellness in a rat model of middle-aged women. To test this hypothesis, female Wistar rats aged 18 months (350-450 g) were orally administered RJ6601 at doses of 200 and 400 mg/kg BW for 28 days. The anxiolytic, antidepression, and memory-enhancing effects were assessed every 7 days throughout the study period. The neuron density and levels of activities of AChE, total MAO, MAO-A, MAO-B, MDA, SOD, CAT, GSH-Px, IL-1β, IL-6, and BDNF in the prefrontal cortex at the end of study were also investigated. Furthermore, the amounts of Lactobacillus spp. and Bifidobacterium spp. in their feces were also determined. The results revealed that the developed soup shows anxiolytic, antidepression, and memory-enhancing effects. An increased neuron density; reductions in AChE, total MAO, MAO-A, MAO-B, and MDA; and an elevation of serum BDNF, together with increased amounts of both bacterial species in feces, were also observed. Our results suggest that RJ6601 is a potential mental wellness promotion supplement that enhances BDNF levels, brain plasticity, neurotransmitter balance, and oxidative stress and inflammation status, along with improving microbiota.

Biochemical Characteristics of Pharmacologically Induced Hind Limb Paralysis in CD-1 Mice

A model of pharmacological paralysis in the hind limbs of CD-1 mice was introduced. In the initial phase (before paralysis), the activity of MAO-A, a key enzyme of neuroamine metabolism, was inhibited, leading to increased levels of steroid hormones and prolactin, as well as to a decrease in hepatic CYP3A4 and CYP2D6 activities and astrocytic S-100 protein secretion into the blood serum. In the second phase (paralysis manifestation), the mice exhibited hind limb paralysis development, accumulation of cortisol granules, destruction of capillaries, and aggregation of deformed red blood cells in the cerebral cortex and hippocampal regions.

Key Enzymes of the Serotonergic System - Tryptophan Hydroxylase2 and Monoamine OxidaseA - In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153.

At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. Theaim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes- tryptophan hydroxylase2 (TPH2) and monoamine oxidaseA (MAOA)- in the brain of aggressive and tame rats. Either TC-2153 (10 or 20mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them intame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.