Decreased Monoamine Oxidase Activity Research Articles

Nitric oxide interacts with monoamine oxidase to modulate aggression and anxiety-like behaviour

Nitric oxide (NO) is a gaseous neurotransmitter that has important behavioural functions in the vertebrate brain. In this study we compare the impact of decreased nitric NO signalling upon behaviour and neurobiology using both zebrafish and mouse. nitric oxide synthase mutant (nos1−/−) zebrafish show significantly reduced aggression and an increase in anxiety-like behaviour without altered production of the stress hormone cortisol. Nos1−/− mice also exhibit decreased aggression and are hyperactive in an open field test. Upon reduction of NO signalling, monoamine neurotransmitter metabolism is reduced as a consequence of decreased Monoamine oxidase activity. Treatment of nos1−/− zebrafish with the 5-HT receptor 1A agonist 8-OH-DPAT rescues aggression and some aspects of anxiety-like behaviour. Taken together, the interplay between NO and 5-HT appears to be critical to control behaviour. Our cross-species approach challenges the previous notion that reduced neuronal NOS leads to increased aggression. Rather, Nos1 knock-out can also lead to decreased aggression in some situations, a finding that may have implications for future translational research.

Effects of dietary methylmercury on the dopaminergic system of adult fathead minnows and their offspring.

Mercury (Hg) is a ubiquitous environmental contaminant and potent neurotoxin, which may be transformed by bacteria in aquatic ecosystems to methylmercury (MeHg), an organic form which bioaccumulates and biomagnifies. Consequently, long-lived organisms at the top of the food web are at risk of dietary MeHg exposure, which can be actively transferred from mother to offspring. Exposure during neurodevelopment can lead to serious, irreversible neurological dysfunction, associated with a variety of cognitive and motor abnormalities. At low dietary concentrations, MeHg exposure has been associated with deficits in attention and hyperactivity in multiple species. Pathways associated with cognitive function and motor activity are primarily associated with the dopaminergic system. The present study used a model fish species, Pimephales promelas, to examine the effects of MeHg exposure on dopamine concentrations and monoamine oxidase activity in embryos and adult brains. Adult fatheads were exposed for 30 d to either a control or a treated diet (0.72 ppm Hg). Embryonic and larval exposures were a result of maternal transfer of dietary MeHg. The authors confirmed hyperactive behaviors in embryos and detected significant changes in embryonic dopamine concentrations. Similar effects on dopamine concentrations were seen in the telencephalon of adult brains. Exposure to MeHg also corresponded with a significant decrease in monoamine oxidase activity in both embryos and brain tissue. Collectively, these results suggest that current exposure scenarios in North America are sufficient to induce alterations to this highly conserved neurochemical pathway in offspring, which may have adverse effects on fish behavior and cognition. Environ Toxicol Chem 2017;36:1077-1084. © 2016 SETAC.

Serotonin Metabolism in the Placenta in Exacerbation of Herpesvirus Infection during Pregnancy

Serotonin metabolism in the blood and placental homogenate was studied in pregnancy aggravated by exacerbation of herpesvirus infection. Blood serotonin content in pregnant patients increased with increasing herpesvirus antibody titers and reduction of monoamine oxidase activity. Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) decreased. The decrease of monoamine oxidase activity in placental homogenate led to an increase of serotonin level, which was paralleled by destruction of mitochondria in the syncytiotrophoblast, suppression of BCL-2 protein activity, and increase of caspase-3 level.

Physiological and biochemical effects of 17β estradiol in aging female rat brain

Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease. These changes increase during menopausal condition in females when the level of estradiol is decreased. The objective of this study was to observe the changes in activities of monoamine oxidase, glucose transporter-4 levels, membrane fluidity, lipid peroxidation levels and lipofuscin accumulation occurring in brains of female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of estradiol (0.1 μg/g body weight for 1 month). The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, lipid peroxidation levels and lipofuscin accumulation in the brains of aging female rats, and a decrease in glucose transporter-4 level and membrane fluidity. Our data showed that estradiol treatment significantly decreased monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in brain regions of aging rats, and a reversal of glucose transporter-4 levels and membrane fluidity was achieved, therefore it can be concluded from the present findings that estradiol's beneficial effects seemed to arise from its antilipofuscin, antioxidant and antilipidperoxidative effects, implying an overall anti-aging action. The results of this study will be useful for pharmacological modification of the aging process and applying new strategies for control of age related disorders.

Inhibition of monoamine oxidase activity by cannabinoids

Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and psychotropic drugs, including cannabinoids. This study investigated in vitro effects of cannabinoids on the activity of monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters and affecting brain development and function. The effects of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), the endocannabinoid anandamide (N-arachidonoylethanolamide [AEA]), and the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) on the activity of MAO were measured in a crude mitochondrial fraction isolated from pig brain cortex. Monoamine oxidase activity was inhibited by the cannabinoids; however, higher half maximal inhibitory concentrations (IC(50)) of cannabinoids were required compared to the known MAO inhibitor iproniazid. The IC(50) was 24.7 micromol/l for THC, 751 micromol/l for AEA, and 17.9 micromol/l for WIN when serotonin was used as substrate (MAO-A), and 22.6 micromol/l for THC, 1,668 micromol/l for AEA, and 21.2 micromol/l for WIN when phenylethylamine was used as substrate (MAO-B). The inhibition of MAOs by THC was noncompetitive. N-Arachidonoylethanolamide was a competitive inhibitor of MAO-A and a noncompetitive inhibitor of MAO-B. WIN was a noncompetitive inhibitor of MAO-A and an uncompetitive inhibitor of MAO-B. Monoamine oxidase activity is affected by cannabinoids at relatively high drug concentrations, and this effect is inhibitory. Decrease of MAO activity may play a role in some effects of cannabinoids on serotonergic, noradrenergic, and dopaminergic neurotransmission.

Hyperserotonergic phenotype after monoamine oxidase inhibition in larval zebrafish

Serotonin (or 5-hydroxytryptamine; 5-HT) and monoamine oxidase (MAO) are involved in several physiological functions and pathological conditions. We show that the serotonergic system and its development in zebrafish are similar to those of other vertebrates rendering zebrafish a good model to study them. Development of MAO expression followed a similar time course as the 5-HT system. MAO expression and activity were located in or adjacent to serotonergic nuclei and their targets, especially in the ventral hypothalamus. MAO mRNA was detected in the brain from 24 h post-fertilization and histochemical enzyme activity from 42 h post-fertilization. Deprenyl (100 microM) decreased MAO activity 34-74% depending on the age. Inhibition of MAO by deprenyl strongly increased 5-HT but not dopamine and noradrenaline levels. Deprenyl decreased 5-HT-immunoreactivity in serotonergic neurons and induced novel ectopic 5-HT-immunoreactivity neurons in the diencephalon in a manner dependent on 5-HT uptake. Deprenyl administration decreased locomotion, altered vertical positioning and increased heart rate. Treatment with p-chlorophenylalanine normalized 5-HT levels and rescued the behavioral alteration, indicating that the symptoms were 5-HT dependent. These findings suggest that zebrafish MAO resembles mammalian MAO A more than MAO B, metabolizing mainly 5-HT. Applications of this model of hyperserotonergism include pharmacological and genetic screenings.

Influence of prolonged fasting on monoamine oxidase and semicarbazide-sensitive amine oxidase activities in rat white adipose tissue

Monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) activities are very high in white adipose tissue (WAT). SSAO, also known as Vascular Adhesion Protein-1 in vessels, is present at the surface of fat cells and independent approaches have evidenced its impressive increase during adipogenesis. However, the factors that might regulate the expression SSAO and MAO in adipose tissue are still poorly defined. Here, we report the influence of fasting on MAO and SSAO activities in adipose depots. A decrease of MAO activity occurred after three days of starvation in the intra-abdominal adipose tissue (INWAT) of male Wistar rats, regardless of their initial adiposity or fat loss. The reduced fat stores of seven-week old rats, loosing 59 % of INWAT mass during fasting, contained only one half of the MAO activity found in fed control. The same reduction of MAO was observed after prolonged fasting in older rats which lose only 26% of their INWAT during the same starvation duration, leading to a fat mass comparable to that of younger fed control rats. It was therefore the endocrine and metabolic changes occurring during fasting that were responsible for the reduced MAO activity and not the amount of INWAT. Surprisingly, SSAO activity remained unchanged during starvation. In subcutaneous WAT, the changes in MAO and SSAO activities exhibited the same tendencies than those found in INWAT. Taken together, these data show that both MAO and SSAO activities increase in INWAT with age-dependent fattening, and indicate that only MAO diminishes during fasting.

Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats

The effects of anti-inflammatory drugs on ileal 5-hydroxytryptamine (5-HT) metabolic dynamics at 72 h after a single administration of cisplatin were investigated in rats. Cisplatin 5 mg/kg i.p. caused pathological changes, with an inflammatory response occurring 72 h after its administration. The inflammatory response was associated with the induction of cyclooxygenase-2, but not cyclooxygenase-1, in the ileal mucosa at 72 h after the cisplatin administration. Daily treatment with meloxicam 3 mg/kg s.c. ameliorated the cisplatin-induced mucosal damage, whereas dexamethasone 1 mg/kg s.c. did not. Cisplatin administration also caused a significant increase in cyclooxygenase-2 mRNA expression at 72 h after administration, which was blunted by dexamethasone, but not by meloxicam. Cisplatin increased the content of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), but had no effect on 5-HT turnover (5-HIAA/5-HT ratio). Meloxicam and dexamethasone did not significantly decrease 5-HT and 5-HIAA content. Cisplatin significantly decreased monoamine oxidase activity but increased tryptophan hydroxylase (TPH) activity and TPH 1 mRNA expression in ileal tissue. Meloxicam and dexamethasone significantly restored the decreased monoamine oxidase activity and inhibited the cisplatin-induced increase in tryptophan hydroxylase activity toward the control levels. These drugs also decreased the cisplatin-induced increase in TPH 1 mRNA expression. Neither cisplatin nor the anti-inflammatory drugs had significant effect on mRNA expression of the serotonin re-uptake transporter. These results suggest that the inflammatory response associated with cyclooxygenase-2 induction is involved in the opposite change in ileal tryptophan hydroxylase and monoamine oxidase activities in the delayed phase after single administration of cisplatin to rats.

Effect of dehydroepiandrosterone (DHEA) on monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in aging rat brain regions

Dehydroepiandrosterone (DHEA), one of the major steroid hormones, and its ester have recently received attention with regard to aging and age-related diseases like Alzheimer and others. DHEA is synthesized de novo in the brain and its substantial fall with age has been shown to be associated with neuronal vulnerability to neurotoxicity processes. Thus, DHEA is considered to be a neuroactive pharmacological substance with potential antiaging properties. A prominent feature that accompanies aging is an increase in monoamine oxidase (MAO). Increased MAO activity with correlated increase in lipid peroxidation in the aging rat brain supports the hypothesis that catecholamine oxidation is an important source of oxidative stress. The progressive accumulation of lipofuscin in neuronal cells is one of the most characteristic age related changes, an increase in body weight was also observed at 24 months. The objective of this study was to observe the changes in monoamine oxidase activity, lipid peroxidation levels and lipofuscin accumulation occurring in aging rat brain regions, and to see whether these changes are restored to normal levels after exogenous administration of DHEA (30 mg/kg/day for 1 month). The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, lipid peroxidation levels and lipofuscin accumulation in brain regions of 4, 14 and 24 months age group male rats. The present study showed that DHEA treatment significantly decreased monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in brain regions of aging rats, the increased body weight at 24 months also decreased more than the age matched controls. It can therefore be suggested that DHEA's beneficial effects seemed to arise from its antioxidant, antiobesity, antilipofuscin, antilipidperoxidative and thereby anti-aging actions. The results of this study will be useful for pharmacological modification of the aging process and development of new drugs for age related disorders.

Diabetes induces changes of catecholamines in primary mesangial cells

Diabetes mellitus is a frequent cause of kidney function damage with diabetic nephropathy being predominantly related to glomerular dysfunction. Diabetes is capable of interfering with distinct hormonal systems, as well as catecholamine metabolism. Since mesangial cells, the major constituent of renal glomerulus, constitute a potential site for catecholamine production, the present study was carried out to investigate alterations in catecholamine metabolism in cultured mesangial cells from the nonobese diabetic mouse, a well-established model for type I diabetes. We evaluated mesangial cells from normoglycemic and hyperglycemic nonobese diabetic mice, as well as cells from normoglycemic Swiss mice as control. Mesangial cells from normoglycemic mice presented similar profiles concerning all determinations. However, cells isolated from hyperglycemic animals presented increased dopamine and norepinephrine production/secretion. Among the studied mechanisms, we observed an upregulation of tyrosine hydroxylase expression accompanied by increased tetrahydrobiopterin consumption, the tyrosine hydroxylase enzymatic cofactor. However, this increase in synthetic pathways was followed by decreased monoamine oxidase activity, which corresponds to the major metabolic pathway of catecholamines in mesangial cells. In addition, whole kidney homogenates from diabetic animals also presented increased dopamine and norepinephrine levels when compared to normoglycemic animals. Thus, our results suggest that diabetes alters catecholamine production by interfering with both synthesizing and degrading enzymes, suggesting a possible role of catecholamine in the pathogenesis of acute and chronic renal complications of diabetes mellitus.

Neurotoxicological effects of a primary and ozonated treated wastewater on freshwater mussels exposed to an experimental flow-through system

The neurotoxic potential of a primary-treated and ozonated municipal effluent was examined using feral freshwater Elliptio complanata mussels. Specimens were exposed to increasing concentrations (0, 1, 3, 10 and 20% v/v) of a primary-treated effluent before and after treatment with 10 mg/L of ozone in a mesocosm-type experiment for 30 days. A suite of biomarkers was used to assess the potential neurotoxic stress of the wastewaters on these benthic invertebrates: opiate binding sites, γ-aminobutyric acid (GABA) metabolism, monoamines levels (serotonin, dopamine), monoamine oxidase, acetylcholinesterase and lipid peroxidation. Gametogenic activity was also determined by the gonado-somatic index and by vitellogenin-like proteins. The results show that the number of opiate binding sites increased slightly, especially after ozonation. GABA metabolism was generally reduced, suggesting higher glutamate stimulation than GABA dampening effects in mussel ganglia. This excitatory state was further confirmed by decreased acetylcholinesterase activity in gonadal tissues. The turnover of dopamine was enhanced with increased serotonin levels, but accompanied by reduced catabolism, as evidenced by decreased monoamine oxidase activity. Moreover, oxidative stress was increased, as determined by lipid peroxidation in the gonad (containing ganglia), which was significantly correlated with acetylcholinesterase activity and dopamine metabolism. The gonado-somatic index was significantly reduced with increased levels of vitellogenin-like proteins, again confirming the estrogenic action of these wastewaters. The data suggest that exposure to a primary-treated municipal effluent before and after ozonation leads to an excitotoxic syndrome implicating perturbations in GABA, dopamine and acetylcholine signaling. The increase in dopamine metabolism may be associated with the occurrence of opiate-like compounds (i.e. morphine) in the effluent. In general, ozonation reduced the severity of the responses, indicating that this disinfection strategy does not increase neurotoxicity to mussels.

Biochemical Markers of Neurotoxicity in Wildlife and Human Populations: Considerations for Method Development

Disruption of neurochemical parameters in blood and brain tissues can be used as early biomarkers of neurotoxicity in human and wildlife epidemiological studies. To investigate the feasibility of biomarker measurements in field samples obtained from remote locations, tissue storage limits were determined with human blood and mink cortex tissue using efficient and cost-effective microplate assays. Results show that isolated blood platelets and plasma can be stored at 4°C for 4 wk before measurement of monoamine oxidase (MAO) and cholinesterase (ChE) activities, while human lymphocytes can be stored at 4°C for up to 2 d before muscarinic acetylcholine (mACh) receptor binding analysis. Blood cells stored frozen resulted in decreased MAO activity and mACh receptor function. These data suggest that mink brain tissue obtained from field samples can be stored at various temperatures without affecting dopamine (D2) and mACh receptor densities; however, MAO and ChE activities were most stable in samples stored in a −20°C domestic freezer or at 4°C. Multiple freeze/thaw cycles alter mACh and D2 receptors and MAO activity in mink cortex samples and should therefore be minimized. In conclusion, these neurochemical biomarkers can efficiently be measured in large human and wildlife neurotoxicity studies, provided proper storage conditions are maintained. This study was financially supported by the Collaborative Mercury Research Network (COMERN) and the Natural Science and Engineering Research Council (NSERC) of Canada. C. J. Stamler and N. Basu are both recipients of NSERC postgraduate fellowships. We also thank Mary Gamberg (Gamberg Consulting, Whitehorse, Yukon Territory) and Dr. Steven J. Bursian (Michigan State University, East Lansing) for kind donation of mink tissues. Assistance by Donna Leggee, Leah Tivoli, Kovana M. Loua, and Stephanie Bailey is greatly appreciated.

The Effect of Diabetes Mellitus on the Morphology and Physiology of Monoamine Oxidase in the Pancreas

Monoamine oxidase (MAO) is an ubiquitous, non-soluble, membrane-bound enzyme, located in the outer membrane of mitochondria. MAO consists of two subtypes, MAO-A and MAO-B, depending on their substrates and sensitivity to inhibitors. MAO consists of two units joined together by a disulphide bond. The two units of MAO and flavin adenine dinucleotide (FAD) form a polymer in the outer membrane of mitochondria. The function of MAO-A is highly dependent on the lipid constituent of mitochondrial membrane, whereas the function of MAO-B does not depend on the lipid status of mitochondrial membrane. Hydrogen peroxide and ammonia are generated during MAO-induced metabolism of its substrates. MAO and its substrates are present in both the exocrine as well as the endocrine parts of the pancreas. In the islet of Langerhans, MAO-A is observed in about 50% of the cells, whereas MAO-B is less abundant and located mainly in the periphery of pancreatic islets. MAO-B is also demonstrated in centroacinar cells and in pancreatic ducts. Electron microscopy studies suggest that MAO is co-localised with insulin in secretory granules of pancreatic beta cells. Pharmacologically, beta-2-adrenoreceptors agonists such as terbutaline can stimulate MAO activity. In contrast, cholinergic muscarinic stimulation does not affect islet MAO activity. MAO activity in pancreatic tissue is significantly reduced in diabetes. This decrease in MAO activity is associated with an increase in pancreatic tissue levels of adrenaline (ADR) and noradrenaline (NA). Studies on the level of 5-hydroxyindoleacetic acid of pancreatic tissues suggest that serotonin level is also increased in diabetics. Many studies show that MAO inhibits insulin secretion. However, some of its substrates including, serotonin, adrenaline and noradrenaline have been shown to stimulate insulin secretion. In conclusion, the activity and subcellular localisation of MAO suggests that MAO may play an important role in pancreatic beta cell function and hence in the pathogenesis of diabetes mellitus.

INTESTINAL DOPAMINERGIC ACTIVITY IN OBESE AND LEAN ZUCKER RATS: RESPONSE TO HIGH SALT INTAKE

The present study examined intestinal dopaminergic activity and its response to high salt (HS, 1% NaCl over a period of 24 hours) intake in obese (OZR) and lean Zucker rats (LZR). The basal Na+,K+-ATPase activity (nmol Pi/mg protein/min) in the jejunum of OZR was higher than in LZR on normal salt (NS) (OZR-NS=111.3±6.0 vs. LZR-NS=88.0±8.3). With the increase in salt intake, the basal Na+,K+-ATPase activity significantly increased in both animals (OZR-HS=145.9±11.8; LZR-HS=108.8±6.7). SKF 38393 (10 nM), a specific D1-like dopamine receptor agonist, inhibited the jejunal Na+,K+-ATPase activity in OZR on HS intake, but failed to inhibit enzyme activity in OZR on NS intake and LZR on NS and HS intakes. The aromatic L-amino acid decarboxylase (AADC) activity in OZR was lower than in LZR on NS intake. The HS intake increased AADC activity in OZR, but not in LZR. During the NS intake the jejunal monoamine oxidase (MAO) activity in OZR was similar to that in LZR. The HS intake significantly decreased MAO activity in both OZR and LZR. The jejunal COMT activity in OZR was higher than in LZR on NS intake. The HS intake reduced COMT activity in OZR but not LZR. It is concluded that inhibition of jejunal Na+,K+-ATPase activity through D1 dopamine receptors is dependent on salt intake in OZR, whereas in LZR, the enzyme failed to respond to the activation of D1 dopamine receptors irrespective of their salt intake.

Modulation of MAO activity by imidazoline and guanidine derivatives.

I2-binding sites (I2-BS) are attributed to be a regulative site on monoamine oxidase (MAO). The in vivo and in vitro effects of various imidazoline and guanidine derivatives on MAO activity and on mitochondrial respiration were studied. Substances with high affinity for I2-BS (antazoline, idazoxan, and cirazoline: IC50 = 20.3, 33.8, and 43.4 microM) had a stronger inhibitory effect on MAO activity than did I1-ligands (efaroxan, rilmenidine, clonidine, and moxonidine: IC50 = 277, 801, 1,224, and > 10,000 microM). Substances with the highest inhibitory effects were BDF8082 (IC50 = 1.7 microM) and 2-(2-benzofuranyl)-2-imidazoline (BFI; IC50 = 4.0 microM). The enzyme is inhibited noncompetitively and is reversible, because its activity is completely or partially restored after dialysis. Agmatine, the putative endogenous ligand for IBS, also decreased MAO activity (IC50 = 168 microM), whereas its precursor, L-arginine, and its metabolite, putrescine, had no effects. In vitro inhibition of MAO and mitochondrial respiration by the IBS-ligands tested could not be correlated, suggesting no link between the function of the inner and outer mitochondrial membrane. MAO activity in vivo was significantly reduced only by pargyline (-95%), BDF8082 (-68%), BFI (-43%), and 1-(m-chlorophenyl)-biguanide (-28%). Catecholamine content of livers obtained from animals treated with different IBS-ligands was consequently increased. In conclusion, the strong inhibitory effects of I2 selective imidazoline ligands confirm the existence of I2-BS as a regulatory site on MAO.

Upregulation of the Aromatic Amino Acid Decarboxylase under Neonatal Asphyxia

Perinatal hypoxic–ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to asphyxia. However, the respective enzyme activities have not yet been measured in the living neonatal brain. In this study, we have used18F-labeled 6-fluoro-l-3,4-dihydroxyphenylalanine (FDOPA) together with positron-emission tomography (PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine (DA), in the brain of newborn piglets. Simultaneously, the cerebral blood flow (CBF) was measured with colored microspheres. Asphyxia elicited an up to threefold increase of the CBF. Despite this, the blood–brain transfer of FDOPA as well as the clearance rate constants from brain were unchanged. However, the synthesis rate of FDA from FDOPA was significantly increased in frontal cortex, striatum, and midbrain. This increase of the AADC activity and the decrease of monoamine oxidase activity may contribute to the increase of extracellular DA during asphyxia which is expected to be involved in severe disturbances of neuronal metabolism, e.g., by generating free radicals.

Changes in brain MAO activity and glycogen levels upon chronic alcoholization of three successive generations of rats.

Changes in neurobiological parameters were examined from early life (10 days post-natal) until late adulthood (8 months post-natal) in three successive generations of alcoholized rats. The mean daily consumption of alcohol by the 2nd and 3rd generation rats (7.40 +/- 0.22 and 7.70 +/- 0.20 g ethanol/kg body weight, respectively) was significantly greater than that of the 1st generation alcoholized group (4.26 +/- 0.33 g/kg). Brain/body weight ratios of alcoholized rats, 10 days post-natal, were significantly greater than controls, with 1st generation alcoholized rats presenting significantly greater brain/body weight ratios than those of the 2nd or 3rd generation, which tended toward control weights and ratios. This difference between alcoholized rats and controls persisted, although to a lesser extent, at 8 months post-natal. Glycogen content in the brains of rats of all alcoholized generations was significantly lower than in controls at 10 days post-natal, with a reversal of this situation in later life for 2nd and 3rd generation rats, which presented significantly greater cerebral glycogen levels than control or 1st generation alcoholized rats (which had an equivalent cerebral glycogen content). In 10-day-old rat pups, monoamine oxidase (MAO) activity in brain tissues had a tendency (mostly non-significant) to be greater in alcoholized rats than in controls, with a reversal of this situation, ie a statistically significant decrease in MAO activity in the 2nd and 3rd alcoholized generations with respect to controls, in 8-month-old rats. MAO activity in adrenal glands of alcoholized rats was greater than in controls at 10 days post-natal, and this difference persisted at 8 months.

Biotransformation of furaltadone by pig hepatocytes and Salmonella typhimurium TA 100 bacteria, and the formation of protein-bound metabolites.

1. The major metabolite resulting from the biotransformation of furaltadone (5-morpholinomethyl-3-[5-nitrofurfurylidene-amino]-2-oxazoli dinone) by pig hepatocytes was shown to result from the N-oxidation of the tertiary nitrogen in the morpholino-ring, leaving the nitrofuran ring unchanged. 2. No evidence could be obtained for the formation of an open-chain cyano-metabolite, a minor metabolite in the case of the related nitrofuran drug furazolidone (N-(5-nitro-2-furfurylidene)-3-amino-2-oxazolidinone). This metabolite was the major metabolite, following incubation of furaltadone and furazolidone with Salmonella typhimurium bacteria. 3. The N-oxide was not further metabolized by pig hepatocytes or bacteria, and gave negative test results in the Ames-test (TA 100, no S9-mix) at the highest tested dose of 1 microgram/plate. Furaltadone gave a positive result at 10 ng/plate. 4. The biotransformation of both drugs by pig hepatocytes and bacteria resulted in the formation of protein-bound metabolites, with no clear quantitative differences between the two drugs. The intact 3-amino-2-oxazolidinone (AOZ) and 5-morpholinomethyl-3-amino-2-oxazolidinone (AMOZ) side-chains of furazolidone and furaltadone, respectively, could be released from these metabolites by mild acid treatment. 5. Hepatocytes incubated with the AMOZ side-chain of furaltadone showed a decreased monoamine oxidase activity at high dose levels (IC50 3.7 mM), whereas exposure to the AOZ side-chain of furazolidone resulted in a clear inhibition at 10,000-fold lower concentrations (IC50 0.5 microM). In the presence of 1% dimethylsulphoxide (DMSO), the MAO-inhibition by AMOZ and especially AOZ was remarkably reduced. 6. It is concluded that protein-bound metabolites containing an intact and releasable side-chain might be present in tissues of animals treated with furaltadone. However, these residues might be of less toxicological concern than those of furazolidone.

Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice

Islet β-cell monoamines are known to influence the insulin-releasing mechanisms. These amines are localized in the insulin-secretory granules and are inactivated by the enzyme monoamine oxidase (MAO), a hydrogen peroxide (H 2O 2)-generating enzyme. The activity of islet MAO may consequently be of importance for insulin secretion. In the present investigation, we studied the relation between islet MAO activity and plasma levels of insulin and glucose in obese ( ob ob ) hyperglycemic mice and their lean littermates. In addition, the effect of glucose on the MAO activity of in vitro-cultured islets was studied. MAO activity was assayed with serotonin, dopamine (DA), and β-phenylethylamine (PEA) as substrates. After an overnight fast in adult (age, 6 months) lean mice, islet MAO activity was increased by 35% to 70%. Plasma levels of glucose and insulin were markedly decreased as expected. However, fasting in adult obese mice either did not affect islet MAO activity (PEA and DA) or induced a slight decrease (serotonin) of approximately 25% ( P < .05). Plasma glucose levels in adult obese mice were not significantly affected by the overnight fast. However, a correlation analysis based on individual adult obese mice (fed and fasted) showed a negative correlation between plasma glucose concentration and islet MAO activity with PEA ( r = −.65, P < .02) and DA ( r = −.66, P < .02), respectively. Further, a positive correlation ( r = +.58, P < .05) was found between glucose level and islet MAO activity when using serotonin as substrate. There was no difference in islet MAO activity with PEA and DA as substrates in fed obese versus fed lean mice. However, in the fasted state, the enzyme activity was 25% to 30% lower in islets of obese mice than in those of lean mice. On the other hand, islet MAO activity with serotonin as substrate was much higher in obese versus lean mice in both fed (+300%) and fasted (+55%) animals. An overnight fast in young (age, 5 weeks) obese mice brought about a marked decrease in plasma levels of insulin and glucose, whereas islet MAO activity was unaffected. Islets from adult obese mice cultured in vitro for 3 days in high (11.1 mmol/L) glucose displayed a decreased MAO activity (12% to 25%) with DA and PEA as substrates when compared with islets cultured at low (2.8 mmol/L) glucose. No effect was observed with serotonin as substrate. The data obtained strongly suggest that glucose negatively modulates islet MAO activity. This in turn may affect insulin secretion through its effects on the monoamine content and possibly the redox state of the β cells. In the obese mouse, the regulatory influence of glucose is apparently disordered, which may be one of several factors contributing to the insulin hypersecretion associated with the obesity syndrome.

Relationship of Gonadal Hormone Administration, Sex, Reproductive Status and Age to Monoamine Oxidase Activity Within the Hypothalamus

Abstract Activity of Type A monoamine oxidase (MAO) was measured in microdissected samples from preoptic-hypothalamic and hindbrain areas of young male and female rats, and aged female rats. Administration of estradiol and progesterone, in doses sufficient to facilitate lordosis behavior and induce a luteinizing hormone surge in ovariectomized, but not castrated rats, was associated with sexually dimorphic changes of MAO activity within the hypothalamus. Forty-two h following estradiol benzoate administration, increased MAO activity was measured in the ventromedial nucleus (VML) and midbrain central gray of females, while decreased MAO activity was measured in the VML and arcuate-median eminence (ArME) of males. Progesterone administration to estradiol benzoate-primed rats was associated with decreased MAO activity in the VML and medial preoptic nucleus (mPOA) of females and decreased activity in the dorsal raphe nucleus of males. Activity of MAO on diestrus, proestrus and estrus was assessed in ten preoptic-hypothalamic and hindbrain sites. Differences between days of the cycle were limited to the mPOA, ArME and VML. While activities were generally lowest at estrus, these areas exhibited different patterns of activity across the cycle. Activity was highest at proestrus in the mPOA and highest at diestrus in the VML and ArME. Activity of MAO in some areas of 25-month old, diestrus rats was altered as compared to young, cycling rats; however, ageing was not associated with widespread changes in MAO activity. In the suprachiasmatic nucleus, aged rats showed approximately 30% less activity than young rats. In the mPOA, VML and ArME, activity in aged females was different from some, but not all, days of the estrous cycle. These results show that MAO activity changes within specific hypothalamic sites when the neuroendocrine axis is altered. Since the changes are present in areas where activity of rnonoaminergic systems is critical for initiating gonadotrophin surges and inducing lordosis behavior, these results provide initial evidence that catabolism of monoamines by MAO may contribute to rnonoaminergic regulation of reproductive function.