MAO Activity Research Articles

Hepatocyte Transplants Improve Liver Function and Encephalopathy in Portacaval Shunted Rats

Rats with portacaval shunt (PCS) are useful experimental models of human hepatic encephalopathy in chronic liver dysfunction. We have previously shown that PCS modifies amine neurotransmitter systems in the CNS and increases voluntary alcohol intake by rats. Hepatocyte transplantation, used in acute liver failure, has recently also been applied to chronic liver diseases, which prompted us to investigate whether the altered brain amine system and the drinking behavior in long-term shunted rats could be normalized by hepatocyte transplants. Hepatocytes, isolated from syngeneic donors by collagenase digestion, were injected (3 × 10(6) cells/rat) into the pancreatic tail region, 6 months after PCS. Hepatic function was evaluated by measuring urine urea and plasma L-histidine concentrations. A free choice test with two bottles (tap water and 10% ethyl alcohol) was performed for 3 days to assess the rats' preference for alcohol. The rats were euthanized 2 months posttransplantation. Brain histamine and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured by radioenzymatic assay and by HPLC-EC, respectively, N-tele-methylhistamine by GC/MS while MAOA and MAOB activities by isotopic procedures. Portacaval shunt rats with hepatocyte transplants gave more urea than before transplantation, with lower plasma L-His levels and higher body weight versus the PCS counterparts. Also, those rats consumed less alcohol. The CNS amines and 5-HIAA concentrations, as well as MAO-B activity, being abnormally high in untreated PCS rats, significantly reduced after PCS hepatocyte treatment. The results support the therapeutic values of hepatocyte transplants in chronic liver diseases and the temporary character of PCS-exerted CNS dysfunctions.

Indole Alkaloids and Semisynthetic Indole Derivatives as Multifunctional Scaffolds Aiming the Inhibition of Enzymes Related to Neurodegenerative Diseases – A Focus on Psychotria L. Genus

Indole alkaloids and synthetic indole derivatives are well known for their therapeutic importance. In fact, preclinical and clinical studies had already demonstrated several pharmacological activities for these compounds. Here, we overview the multifunctional potential of these molecules for the inhibition of enzymes related to neurodegenerative disease: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases A and B (MAO-A and MAO-B). A focus will be given on Psychotria L. genus, considering its reported central effects. Finally, three Psychotria alkaloids, namely desoxycordiofoline (61), bahienoside A (64) and bufotenine (65), along with the synthetic indole derivatives (5S)- 5-(1H-indol-3-ylmethyl)imidazolidine-2,4-dione (66), 5-(1H-indol-3-ylmethyl)-2-thioxoimidazolin-4-one (67), 5-(1Hindol- 3-ylmethyl)-3-methyl-2-thioxoimidazolidin-4-one (68), and methyl 2-(aminoN-(2-(4-methylcyclohex-3-enyl)propan- 2-yl)methanethioamino)-3-(1H-indol-3-yl)propanoate (69), were evaluated in vitro regarding their interactions with AChE, BChE, MAO-A and MAO-B. It was observed that 66 and 68 were able to inhibit MAO-A activity with IC50 value of 8.23 and 0.07 μM. Molecular docking calculations were performed in order to understand the interactions between both ligands (66 and 68) and MAO-A. It was observed that the indole scaffold of both compounds bind into the MAO-A active site in the same orientation, establishing van der Waals contacts with lipophilic amino acids. Additionally, the hydantoin ring of 66 is able to interact by hydrogen bonds with two conserved water molecules in the MAO-A active site, while the methyl-thiohydantoin ring of 68 is within hydrogen bond distance from the hydrogen atom attached to the (N-5) of FAD cofactor. Taking together, our findings demonstrate that the indolyl-hydantoin and indolylmethyl-thiohydantoin rings might consists of good scaffolds for the development of new MAO-A inhibitors possessing neuroprotective properties.

HIV-1 Nef expression in microglia disrupts dopaminergic and immune functions with associated mania-like behaviors

Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties. Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection. Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p<0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p<0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05). HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.

Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system

Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels.

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

Tobacco dependence is difficult to treat, with the vast majority of those who try to quit relapsing within the first year. Improvements in smoking cessation therapies may be achieved by improving current preclinical research methods. However, most experimental tests in animals use nicotine alone, ignoring the 8000 other constituents found in tobacco smoke. To improve on this model, we have used self-administration to test the reinforcing properties of aqueous cigarette smoke extract (CSE) in rats, made by bubbling cigarette smoke through a saline solution. CSE is more potent than nicotine alone in both the acquisition and maintenance of self-administration, but did not exhibit higher progressive ratio responding. Mecamylamine and varenicline had similar potencies to block nicotine and CSE self-administration, indicating the involvement of nicotinic receptors in CSE reinforcement. Following extinction of responding, reinstatement was triggered by exposing animals to a pharmacological stressor, yohimbine (2.5 mg/kg, i.p.), alone and in combination with cues. Animals that self-administered CSE were significantly more sensitive to stress-induced reinstatement than those that self-administered nicotine. Ligand binding autoradiography studies showed nicotine and CSE to have similar affinities for different nicotinic receptor types. CSE significantly reduced MAO-A and MAO-B activities in vitro, whereas nicotine did not. Although CSE inhibition of MAO-A activity in vitro was found to be partially irreversible, irreversible inhibition was not observed in vivo. These experiments show that CSE is an effective reinforcer acting via nicotinic receptors. Furthermore, it better models MAO inhibition and is more sensitive to stress-induced reinstatement than nicotine alone, which is a potent trigger for relapse in smokers.

Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress

BackgroundIn the present study, antidepressant-like activity of palmatine was evaluated in unstressed and stressed young male Swiss albino mice. MethodsThe animals were subjected to unpredictable mild stress daily for 21 successive days to induce depression-like behavior. Palmatine (0.25, 0.5, 1mg/kg, ip) was administered for 21 successive days to unstressed and stressed mice. The antidepressant-like activity was evaluated using the tail suspension test, forced swim test and sucrose preference test. ResultsPalmatine (0.5 and 1mg/kg, ip) significantly decreased immobility periods of unstressed and stressed mice in the forced swim test and tail suspension test, thus indicating its significant antidepressant-like activity. Only the highest dose (1mg/kg) of palmatine significantly reversed the stress-induced decrease in sucrose preference. There was no significant effect on locomotor activity of the mice by palmatine and fluoxetine. The antidepressant-like activity of palmatine was found to be comparable to fluoxetine (10mg/kg) administered for successive 21 days. Palmatine (0.5 and 1mg/kg, ip) significantly reversed the stress-induced increase in brain catalase levels, MAO-A activity, lipid peroxidation, plasma nitrite and corticosterone levels. ConclusionsPalmatine showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of MAO-A activity, decrease in plasma nitrite levels and due to its antioxidant activity. In addition, palmatine also showed antidepressant-like activity in stressed mice probably through decrease in plasma corticosterone levels.

Effect of static and alternating magnetic fields on acetylcholinesterase and monoamine oxidase activities in the brain of mice

Background. Exposure to magnetic fields (MFs) can affect the release of neurotransmitters, such as acetylcholine, serotonin and dopamine in the brain. Objective. To study some biochemical changes associated with the exposure to low frequency static and alternating MFs at a flux density of 3 mT. Methods. Forty male mice were included in this study. Thirty mice were exposed to a combination of static and alternating MFs at a flux density of 3 mT for duration of 1 to 3 weeks. Ten mice were taken as a control group. Activities of acetylcholine esterase (AchE) and monoamine oxidase (MAO) enzymes were determined in whole brain homogenates of these mice. Results. The activities of both enzymes were significantly increased in mice exposed to the magnetic fields compared to the control group. These changes were more apparent after three weeks of exposure and were associated with some behavioral manifestations. No mortality or body weight changes were reported after MF exposure. In the present study, the enzymatic activities of AchE and MAO-A & -B were found to be significantly increased in brains of mice exposed to low frequency magnetic fields (LFMF). Conclusion. Exposure to MF causes changes in the activities of brain enzymes and these changes could affect the behavior of the animals exposed to MF.

Altered Monoamine Metabolism in High Fat Diet Induced Neuropsychiatric Changes in Rats

Objective: To investigate the role of central and peripheral monoamine metabolism on neuropsychological status in high fat diet induced obese rats. Method: Animals were fed on high fat diet for 12 weeks. Periodically blood was collected to estimate serum Metanephrine (MN) levels. After 11 weeks, behavioural paradigms of depression, locomotor activity and cognition were performed. Central (brain) and peripheral i.e. Visceral White Adipose Tissue (vWAT) and Brown Adipose Tissue (BAT) MN levels, Monoamine Oxidase A and B (MAO-A, MAO-B) enzyme activity and Acetylcholinesterase (AChE) activity was estimated. Results: High fat diet significantly increased the body weight which was negatively correlated with the serum metanephrine concentration. However, metanephrine concentration in brain was significantly decreased whereas it significantly increased in vWAT with no change in BAT. In obese animals, immobility time in forced swim test and transfer latency in elevated plus maze was significantly increased while locomotor activity was significantly decreased. Central MAO-A and MAO-B activities were increased while enzyme activities showed a significant reduction in vWAT with no change in BAT. Brain AChE activity was also increased significantly in obese rats. Conclusion: Metabolism of biogenic monoamines plays a critical role in altered neuropsychiatric behaviours associated with diet induced obesity.

향사양위탕이 시스플라틴 유발 랫트의 위장관 기능 장애에 미치는 영향

Beneficial Effect of Hyangsayangwi-tang on the Cisplatin-Induced Gastrointestinal Dysfunctions in Rats Eun-Hee Seo, Seong-Tae Kim, Na-Young Bae, Ae-Ryun Choi Dept. of Sasang Constitutional Medicine, College of Oriental Medicine, Daegu Haany Univ. Dept. of Sasang Constitutional Medicine, Div. of clinical medicine, School of Korean Medicine, Pusan National University Objectives This study aimed to observe the effect of Hyangsayangwi-tang on the cisplatin-induced gastrointestinal dysfunctions in rats. Methods Four groups(each of 8 rats per group) were used in this study. Saline and distilled water treated control rats are Intact vehicle control group. Delayed gatrointestinal mortility was induced by intraperitoneal treatment of cisplatin 2mg/kg, once a week for 5 weeks(Cisplatin control group). Hyangsayangwi-tang aqueous extracts(HY) were orally administered in a volume of 5ml/kg, once a day for 14 days from 4th ciplatin treatmernt(HY group). Ondansetron 1mg/kg was subcutaneously treated, in a volume of 1ml/kg, as same as HY(ondansetron group). We measured the body weights, intestinal charcoal transit ratio, fecal parameters, fundus MDA, GSH contents and SOD, CAT activities, TPH and MAO activities, pyloric gastrin and serotonin contents with their immunoraective cells, colonic serotonin-immunoreactive cells, the histopathology of pylorus, fundus mucosa and colon. Results and Conclusions (1) The body weight gains, the small intestinal charcoal transfer rates, the fecal parameters(numbers, weights and water contents) were increased in HY, ondansetron group. (2) The inhibit of fundus antioxidant defense systems by cisplatin were decreased in HY, ondansetron group. (3) The pyloric TPH activities were increased and the pyloric MAO activities were decreased in HY group. (4) The pyloric gastric contents and the gastrin-immunoreactive cells were increased in HY group. And the pyloric serotonin contents and the pyloric and colonic serotonin-immunoreactive cells were decreased in HY group. (5) The pyloru atrophic changes and the gastric surface erosive damage regions by cisplatin were favorably inhibited by treatment of HY. HY, a representative Soeumin prescription improve GI dysfunctions and constipation retarded by cisplatin through modulations of GI enterochromaffin cells, serotonin and gastrin-producing cells and antioxidative systems. Especially HY showed the highest favorable effects more than those of ondansetron.

Intrinsic cardiac adrenergic (ICA) cell density and MAO-A activity in failing rat hearts

The efficiency (work/oxygen consumption) of isolated papillary muscles from failing hearts is reduced. We investigated whether this can be due to an increase of intrinsic cardiac adrenergic (ICA) cell density. The number of ICA cells in the septum and both ventricular walls was determined by tyrosine hydroxylase immunohistochemistry in rats with monocrotaline-induced pulmonary hypertension. We found that the number of ICA cells is about 200,000 per rat heart. ICA cell density was significantly lower in right ventricular myocardium of hypertrophied hearts (P < 0.01). MAO-A enzyme histochemistry and inhibition experiments with clorgyline in papillary muscles were performed to localize the enzyme and to determine its oxygen consumption. Upregulation of MAO-A was found in the right ventricular wall and papillary muscles of failing hearts (P = 0.018). A positive correlation between ICA cell density and MAO-A activity was absent. Clorgyline (2 μM) decreased the basal rate of oxygen consumption of right ventricular papillary muscles by 65 μM O(2)/s (P = 0.027). This rate can only be maintained for several seconds judging from the catecholamine content of the preparations reported previously. High ICA cell activity rather than density and/or recycling of oxidized catecholamines are discussed as alternative explanations for the low myocardial efficiency in experimental pulmonary hypertension.

The protective role of Bax Inhibitor-1 against chronic mild stress through the inhibition of monoamine oxidase A

The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1−/− mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1+/+ mice. BI-1−/− mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1+/+ mice. To examine the involvement of BI-1 in the Ca2+-sensitive MAO activity, thapsigargin-induced Ca2+ release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca2+ release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca2+-associated MAO-A regulation.

Chronic monoamine oxidase-B inhibitor treatment blocks monoamine oxidase-A enzyme activity

Patients with Parkinson's disease receive selective irreversible monoamine oxidase (MAO)-B inhibitors, but their effects on MAO-A activity are not known during long-term application. We determined MAO-A inhibition in plasma samples from patients with MAO-B inhibitor intake or without MAO-B inhibitor treatment and from healthy controls. We detected a 70% reduction of MAO-A activity in patients with MAO-B inhibitor therapy in comparison to the other groups. Our results suggest that treatment with MAO-B inhibitor may also influence MAO-A activity in vivo, when administered daily.

The MAO-A inhibitor clorgyline reduces ethanol-induced locomotion and its volitional intake in mice

Hydrogen peroxide is the co-substrate used by the enzyme catalase to form Compound I (the catalase–H2O2 system), which is the major pathway for the conversion of ethanol (EtOH) into acetaldehyde in the brain. This acetaldehyde has been involved in many of the effects of EtOH. Previous research demonstrated that treatments that change the levels of cerebral H2O2 available to catalase modulate the locomotor-stimulating effects of EtOH and its volitional intake in rodents. However, the source of H2O2 which is used by catalase to form Compound I and mediates the psychoactive actions of EtOH is unknown. One cause of the generation of H2O2 in the brain comes from the deamination of biogenic amines by the activity of MAO-A. Here we explore the consequences of the administration of the MAO-A inhibitor clorgyline on EtOH-induced locomotion and voluntary EtOH drinking. For the locomotor activity tests, we injected Swiss (RjOrl) mice intraperitoneally (IP) with clorgyline (0–10mg/kg) and later (0.5–8h) with EtOH (0–3.75g/kg; IP). Following these treatments, mice were placed in locomotor activity chambers to measure their locomotion. For the drinking experiments, mice of the C57BL/6J strain were injected IP with clorgyline prior to offering them an EtOH (20%) solution following a drinking-in-the-dark procedure. Additional experiments were performed to assess the selectivity of this compound in altering EtOH-stimulated locomotion and EtOH intake. Moreover, we indirectly tested the ability of clorgyline to reduce brain H2O2 levels. We showed that this treatment selectively reduced EtOH-induced locomotion and its self-administration. Moreover, this compound decreased central H2O2 levels available to catalase. We suggest that H2O2 derived from the deamination of biogenic amines by the activity of MAO-A could determine the formation of brain EtOH-derived acetaldehyde. This centrally-formed acetaldehyde within the neurons of the aminergic system could play a role in the neurobehavioral properties of EtOH.

MicroRNA-142 Reduces Monoamine Oxidase A Expression and Activity in Neuronal Cells by Downregulating SIRT1

Aberrant expression of microRNAs (miRs) has been implicated in the pathogenesis of several neurodegenerative disorders. In HIV-associated neurocognitive disorders (HAND), miR-142 was found to be upregulated in neurons and myeloid cells in the brain. We investigated the downstream effects of chronic miR-142 upregulation in neuronal cells by comparing gene expression in stable clones of the human neuroblastoma cell line BE(2)M17 expressing miR-142 to controls. Microarray analysis revealed that miR-142 expression led to a reduction in monoamine oxidase (MAO) A mRNA, which was validated by qRT-PCR. In addition to the mRNA, the MAOA protein level and enzyme activity were also reduced. Examination of primary human neurons revealed that miR-142 expression indeed resulted in a downregulation of MAOA protein level. Although MAOA is not a direct target of miR-142, SIRT1, a key transcriptional upregulator of MAOA is, thus miR-142 downregulation of MAOA expression is indirect. MiR-142 induced decrease in MAOA expression and activity may contribute to the changes in dopaminergic neurotransmission reported in HAND.

Antidepressant-like activity of turmerone in behavioral despair tests in mice

BackgroundThe present study was undertaken to evaluate the anti-depressive activity of turmerone after one-week administration by using a mouse forced swimming test (FST) and tail suspension test (TST).MethodsAnimals were divided into four groups (n = 10 /group): control (0.9% saline), the three doses of turmerone (1.25, 2.5, 5.0 mg/kg) for one-week treatment. To assess the effect of turmerone on locomotor activity, mice were evaluated in the open-field paradigm. Forced swimming test (FST) and Tail suspension test (TST) were used to take as a measure of antidepressant activity. The probable mechanisms of action of the anti-depressive effect of turmerone was also investigated by measuring the activity of monoamine oxidase-A and corticosterone levels in the blood and the levels of monoamines in the cortex, striatum, hippocampus and hypothalamus of the mice.ResultsTurmerone (2.5, 5.0 mg/kg, p.o.) significantly reduced the immobility time of mice in both the FST and TST, but it did not significantly affect the ambulatory and total movements of mice. However, hyperactivity might explain the results. In addition, turmerone decreased the corticosterone level in the blood while it increased the levels of 5-HT in cortex, striatum, hippocampus, and hypothalamus, the level of NE in striatum and hippocampus, the levels of MHPG and DOPAC in hypothalamus, the level of 5-HIAA in striatum, and the level of DA in striatum, hippocampus, and hypothalamus. Turmerone (2.5, 5.0 mg/kg) decreased the activity of MAO-A in the frontal cortex and hippocampus of mouse brain.ConclusionsAfter one-week administration, turmerone produced antidepressant-like effects. The mechanisms of action of anti-depressive effect of turmerone seemed to involve an increase of the monoamines level decreasing the MAO-A activity and the stress of mice.

Analgesic effect of ferulic acid on CCI mice：behavior and neurobiological analysis

To study the analgesic effect of chronic administration with ferulic acid, and preliminarily discuss its mechanism. Thermal hyperalgesia and mechanical allodynia tests were conducted to observe the analgesic effect of chronic administration with ferulic acid on CCI mice. The neurochemical detection method was applied to observe the effect chronic administration with ferulic acid on monoamine neurotransmitter and monoamine oxidase activity. Compared with the normal group, CCI mice showed notable reduction in heat sensation and nociceptive threshold in and mechanical allodynia. Ferulic acid (10, 20, 40 and 80 mg x kg(-1), po) could significantly reverse the situations. In an in-depth study, we found that the reason for these results was that ferulic acid was dose-dependent in increasing 5-HT and NE levels in hippocampus, frontal cortex and amygdale and could inhibit MAO-A activity in mouse brains. These results showed that ferulic acid has the analgesic effect. Its mechanism may be related to the inhibition of monoamine oxidase activity and the increase in monoamine neurotransmitter in mouse brains.

A representative prescription for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats

Ethnopharmacological relevanceDing-Zhi-Xiao-Wan (DZ, also known as Kai-Xin-San) is a famous traditional Chinese medicine used for the treatment of emotional disease. Previously, we have found that in a variety of animal models of depression (such as tail suspension model, model of chronic fatigue and forced swimming model) DZ demonstrated significant antidepressant behavior and promoted the production of 5-hydroxytryptamine (5-HT). However, the mechanisms of 5-HT regulation are still unclear. Therefore, the current study is designed to further investigate the antidepressant effect of DZ by observing its influence on 5-HT synthesis, metabolism, transport and other key links, so as to clarify the molecular mechanism of its 5-HT regulation. Materials and methodsSolitary rising combined with the chronic unpredictable mild stress (CMS) was used to establish the rat model of depression. The rats were given DZ for 3 weeks, the behavior change and the following items in hippocampus and prefrontal cortex were detected simultaneously: 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and 5-HT transporter (5-HTT) were observed. ResultsOur results showed that treatment with the DZ significantly improved the behavior and simultaneously increased the 5-HT level in the hippocampus, prefrontal cortex tissues and hippocampus extracellular of depressive rats. In future studies revealed that DZ could significantly increase the protein and mRNA expression of the key enzymes TPH during the 5-HT synthesis process in the hippocampus and prefrontal cortex of the depressed rats, and suppress the expression of 5-HTT protein and mRNA at the same time. But it had no effects on MAO-A and MAO-B activities. ConclusionWe believe that antidepressant effect of DZ is caused by the increase of 5-HT synthesis and reduction of 5-HT re-uptake, and eventually increase the content of 5-HT in the brain and the synaptic gaps.

Exposure of cardiomyocytes to angiotensin II induces over-activation of monoamine oxidase type A: Implications in heart failure

Several evidences indicate that increased cardiac mitochondrial monoamine oxidase type A (MAO-A) activity associates with a failing phenotype. Till now, the mechanism underlying such relation is largely unknown. We explored the hypothesis that exposure of cardiomyocytes to AT-II caused activation of MAO-A and also of catalase and aldehyde dehydrogenase activities, enzymes involved in degrading MAO's end products.Left ventricular cardiomyocytes were isolated from normoglycemic (N) and streptozotocin-injected (50mg/kg) rats (D) treated or not treated with losartan (20mg/kg/day in drinking water; DLos and NLos, respectively), a type 1 receptor (AT1) antagonist, for 3 weeks. In each group of cells, MAO, catalase and aldehyde dehydrogenase activities were measured radiochemically and spectrophotometrically. The same enzymes were also measured in HL-1 immortalized cardiomyocytes not exposed and exposed to AT-II (100nM for 18h) in the absence and in the presence of irbesartan (1μM), an AT1 antagonist. MAO-A catalase and aldehyde dehydrogenase activities were found significantly higher in D, than in N cells. MAO-A positively correlated with catalase activity in D cells. MAO-A and aldehyde dehydrogenase but not catalase over-activation, were prevented in DLos cells. Similarly, MAO-A activity, but not catalase and aldehyde dehydrogenase increased significantly in HL-1 cells acutely exposed to AT-II and this increase was prevented when irbesartan, an AT1 antagonist was present. Over-activation of cardiomyocyte MAO-A activity is among acute (18h) and short-term (2-weeks of diabetes) cardiac effects of AT-II and a novel target of AT1 antagonists, first line treatments of diabetic cardiomyopathy.

Selegiline Reverses Aβ25–35-Induced Cognitive Deficit in Male Mice

Alzheimer's disease (AD) is biochemically characterized by the occurrence of extracellular deposits of amyloid beta peptide (Aβ) and intracellular deposits of the hyperphosphorylated tau protein, which are causally related to the pathological hallmarks senile plaques and neurofibrillary tangles. Monoamine oxidase B (MAO-B) activity, involved in the oxidation of biogenic monoamines, is particularly high around the senile plaques and increased in AD patients in middle to late clinical stages of the disease. Selegiline is a selective and irreversible MAO-B inhibitor and, although clinical trials already shown the beneficial effect of selegiline on cognition of AD patients, its mechanism of action remains to be elucidated. Therefore, we first investigated whether selegiline reverses the impairment of object recognition memory induced by Aβ25-35 in mice, an established model of AD. In addition, we investigated whether selegiline alters MAO-B and MAO-A activities in the hippocampus, perirhinal and remaining cerebral cortices of Aβ25-35-injected male mice. Acute (1 and 10 mg/kg, p.o., immediately post-training) and subchronic (10 mg/kg, p.o., seven days after Aβ25-35 injection and immediately post-training) administration of selegiline reversed the cognitive impairment induced by Aβ25-35 (3 nmol, i.c.v.). Acute administration of selegiline (1 mg/kg, p.o.) in combination with Aβ25-35 (3 nmol) decreased MAO-B activity in the perirhinal and remaining cerebral cortices. Acute administration of selegiline (10 mg/kg, p.o.) decreased MAO-B activity in hippocampus, perirhinal and remaining cerebral cortices, regardless of Aβ25-35 or Aβ35-25 treatment. MAO-A activity was not altered by selegiline or Aβ25-35. In summary, the current findings further support a role for cortical monoaminergic transmission in the cognitive deficits observed in AD.

Development of a novel fluorine-18 labeled deuterated fluororasagiline ([18F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B)

The objective of this study was to synthesize and evaluate a novel fluorine-18 labeled deuterium substituted analogue of rasagiline (9, [18F]fluororasagiline-D2) as a potential PET radioligand for studies of monoamine oxidase B (MAO-B).The precursor compound (6) and reference standard (7) were synthesized in multi-step syntheses. Radiolabeling of 9 was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulfamidate group. The incorporation radiochemical yield from fluorine-18 fluoride was higher than 30%, the radiochemical purity was >99% and the specific radioactivity was >160GBq/μmol at the time of administration.In vitro compound 7 inhibited the MAO-B activity with an IC50 of 173.0±13.6nM. The MAO-A activity was inhibited with an IC50 of 9.9±1.1μM. The fluorine-18 version 9 was characterized in the cynomolgus monkey brain where a high brain uptake was found (275% SUV at 4min). There was a higher uptake in the striatum and thalamus compared to the cortex and cerebellum. A pronounced blocking effect (50% decrease) was observed in the specific brain regions after administration of l-deprenyl (0.5mg/kg) 30min prior to the administration of 9. Radiometabolite studies demonstrated 40% of unchanged radioligand at 90min post injection.An efficient radiolabeling of 9 was successfully established and in the monkey brain 9 binds to MAO-B rich regions and its binding is blocked by the selective MAO-B compound l-deprenyl. The radioligand 9 is a potential candidate for human PET studies.