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Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC , IHMC , and IHNC , and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC 50 ( half-maximal inhibitory concentration ) value of 1.672 μM, followed by IHC2 (IC 50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH 3 , -CH 3 , and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a K i value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC 50 value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC 50  = 0.093 μM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC 50  = 0.11 μM and Pargyline Pargyline IC 50  = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with K i values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease., (© 2023 John Wiley & Sons Ltd.)

It is unclear whether bufotenin (= N,N-dimethyl-serotonin = 5-hydroxy-N,N-dimethyl-tryptamine), a hallucinogenic drug, can act on human cardiac serotonin 5-HT 4 receptors. Therefore, the aim of the study was to examine the cardiac effects of bufotenin and for comparison tryptamine in transgenic mice that only express the human 5-HT 4 receptor in cardiomyocytes (5-HT 4 -TG), in their wild-type littermates (WT) and in isolated electrically driven (1 Hz) human atrial preparations. In 5-HT 4 -TG, we found that both bufotenin and tryptamine enhanced the force of contraction in left atrial preparations (pD2 = 6.77 or 5.5, respectively) and the beating rate in spontaneously beating right atrial preparations (pD2 = 7.04 or 5.86, respectively). Bufotenin (1 µM) increased left ventricular force of contraction and beating rate in Langendorff perfused hearts from 5-HT 4 -TG, whereas it was inactive in hearts from WT animals, as was tryptamine. The positive inotropic and chronotropic effects of bufotenin and tryptamine were potentiated by an inhibitor of monoamine oxidases (50 µM pargyline). Furthermore, bufotenin concentration- (0.1-10 µM) and time-dependently elevated force of contraction in isolated electrically stimulated musculi pectinati from the human atrium and these effects were likewise reversed by tropisetron (10 µM). We found that bufotenin (10 µM) increased the phosphorylation state of phospholamban in the isolated perfused hearts, left and right atrial muscle strips of 5-HT 4 -TG but not from WT and in isolated human right atrial preparations. In summary, we showed that bufotenin can increase the force of contraction via stimulation of human 5-HT 4 receptors transgenic mouse cardiac preparations but notably also in human atrial preparations., (© 2023. The Author(s).)

Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided 9-membered amino-functionalized sulfur-containing heterocycles (dithionine derivatives) in good yields under mild conditions. Propargylamines bearing 5-membered 1,3-dithiolane and 7-membered 1,3-dithiepane rings rearranged in a similar manner yielding 8- and 10-membered S,S -heterocycles, respectively.

In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[ b ][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl ( 5 ), 1-indol-3-yl ( 8 ), and azocino[4,5- b ]quinoline ( 10 ) derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, 5c - h proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog 5g achieved an IC 50 of 1.35 μM, a value close to that of the well-known MAO B inhibitor pargyline.

Serotonin (5-HT) plays an essential role in regulating female reproductive function in many animals. 5-HT accumulates in the mammalian ovary with the involvement of membrane serotonin transporter SERT and is functionally active in the oocytes of growing follicles, but shows almost no activity in follicular cells. In this study, we clarified the interplay between 5-HT membrane transport and its degradation by monoamine oxidase (MAO) in the mammalian ovary. Using pharmacologic agents and immunohistochemical staining of the cryosections of ovaries after serotonin administration in vitro, we demonstrated the activity of transport and degradation systems in ovarian follicles. The MAO inhibitor pargyline increased serotonin accumulation in the granulosa cells of growing follicles, indicating the activity of both serotonin uptake and degradation by MAO in these cells. The activity of MAO and the specificity of the membrane transport of serotonin was confirmed in primary granulosa cell culture treated with pargyline and fluoxetine. Moreover, the accumulation of serotonin is more effective in the denuded oocytes and occurs at lower concentrations than in the oocytes within the follicles. This confirms that the activity of SERT and MAO in the granulosa cells surrounding the oocytes impedes the accumulation of serotonin in the oocytes and forms a functional barrier to serotonin.

Monoamine oxidase enzyme is necessary for the management of brain functions. It oxidatively metabolizes monoamines and produces ammonia, aldehyde and hydrogen peroxide as by-products. Excessive production of by-products of monoamine metabolism generates free radicals which cause cellular apoptosis and several neurodegenerative disorders for example Alzheimer's disease, Parkinson's disease, depression and autism. The inhibition of MAOs is an attractive target for the treatment of neurological disorders. Clinically approved MAO inhibitors for example selegiline, rasagiline, clorgyline, pargyline etc. are irreversible in nature and cause some adverse effects while recently studied reversible MAO inhibitors are devoid of harmful effects of old monoamine oxidase inhibitors. In this review article we have listed various synthesized molecules containing different moieties like coumarin, chalcone, thiazole, thiourea, caffeine, pyrazole, chromone etc. along with their activity, mode of action, structure activity relationship and molecular docking studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Fundamental neurophysiological processes are often studied using Danio rerio fish as a model. A selective inhibitor of striatal-enriched protein tyrosine phosphatase (STEP) reduces serotonin metabolism in the D. rerio brain. Both STEP and serotonin are involved in the development of neurodegenerative behavioral disorders. Reduction or elevation of the serotonin level in the brain of mice caused by the administration of p-chlorophenylalanine or pargyline, respectively, results in a decrease in the level of ptpn5 mRNA in the striatum, ptpn5 being the gene encoding STEP. However, it has not been established whether this occurs in other organisms. We studied the effect of inhibitors of synthesis (p-chlorophenylalanine) and degradation (pargyline) of serotonin on the expression of the ptpn5 gene and the activity of STEP in the brain of D. rerio. The fish were placed in water containing p-chlorophenylalanine (2 mg/L) or pargyline (0.5 mg/L) for 72 hours, and control subjects were kept in aquarium water. The p-chlorophenylalanine treatment decreased the serotonin level in the brain fourfold, whereas pargyline increased the level of this transmitter sixfold. Both p-chlorophenylalanine and pargyline decrease STEP activity in the D. rerio brain, without affecting the level of the ptpn5 mRNA gene. Thus, interaction between STEP and the serotonin system is observed in both mammals and fish, which indicates the similarity of the regulation processes in vertebrates.

Striatal-enriched protein tyrosine phosphatase (STEP), which was initially identified in the striatum, is encoded by the Ptpn5 gene and is expressed in neurons of various structures of the brain. STEP is involved in regulating neuroplasticity, and its expression abnormalities are associated with human neurodegenerative disorders. The STEP inhibitor 8-trifluoromethyl-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) has been shown to affect the serotoninergic system of the brain. However, the influence of the serotoninergic system on the STEP regulation has not been studied yet. The aim of the study was to investigate how pharmacologically induced changes in the brain serotonin (5-HT) level affect Ptpn5 expression and STEP activity in adult male C57BL/6J mice. To modulate the 5-HT level in the brain, the 5-HT synthesis inhibitor p-chlorophenylalanine or 5-HT degradation inhibitor pargyline was administered intraperitoneally for three successive days. Changes in 5-HT concentration in the brain were assayed using high-performance liquid chromatography. The STEP activity was determined spectrophotometrically in the supernatant by the rate of p-nitrophenyl phosphate dephosphorylation in the absence and presence of the selective STEP inhibitor TC-2153. The Ptpn5 mRNA level was determined using quantitative RT-PCR. The Ptpn5 expression level in the striatum was three times higher than in the cortex and hippocampus. Both increases and decreases in brain 5-HT were for the first time associated with a decrease in Ptpn5 mRNA in the striatum. STEP activity in the striatum and cortex was significantly higher than in the hippocampus. However, p-chlorophenylalanine and pargyline did not affect the STEP activity in the brain structures tested. Thus, a new method was proposed to study the STEP activity in the brain and p-chlorophenylalanine and pargyline were shown to decrease Ptpn5 expression in the striatum in mice.

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC 50 , 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ 1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Activity-based protein profiling (ABPP) has become a powerful chemoproteomic technology allowing for the dissection of complex ligand-protein interactions in their native cellular environment. One of the biggest challenges for ABPP is the extension of the proteome coverage. In this chapter a new ABPP strategy dedicated to monoamine oxidases (MAO) is presented. These enzymes are representative examples of flavin-dependent oxidases, playing a crucial role in the regulation of nervous system signaling.

To elucidate the involvement of monoamine oxidase (MAO) in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion, we applied microdialysis technique to the heart of anesthetized rats. Dialysate samples were collected during 30 min of induced ischemia followed by 60 min of reperfusion. We monitored dialysate 3,4-dihydrobenzoic acid (3,4-DHBA) concentration as an index of hydroxyl radical production using a trapping agent (4-hydroxybenzoic acid), and dialysate myoglobin concentration as an index of cardiomyocyte injury in the ischemic region. The effect of local administration of a MAO inhibitor, pargyline, was investigated. Dialysate 3,4-DHBA concentration increased from 1.9 ± 0.5 nM at baseline to 3.5 ± 0.7 nM at 20-30 min of occlusion. After reperfusion, dialysate 3,4-DHBA concentration further increased reaching a maximum (4.5 ± 0.3 nM) at 20-30 min after reperfusion, and stabilized thereafter. Pargyline suppressed the averaged increase in dialysate 3,4-DHBA concentration by ∼72% during occlusion and by ∼67% during reperfusion. Dialysate myoglobin concentration increased from 235 ± 60 ng/ml at baseline to 1309 ± 298 ng/ml at 20-30 min after occlusion. After reperfusion, dialysate myoglobin concentration further increased reaching a peak (5833 ± 1017 ng/ml) at 10-20 min after reperfusion, and then declined. Pargyline reduced the averaged dialysate myoglobin concentration by ∼56% during occlusion and by ∼41% during reperfusion. MAO plays a significant role in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion.

The temperature of habitat water has a drastic influence on the behavioral, physiological and biochemical mechanisms of crustaceans. Hyperglycemia is a typical response of many aquatic animals to harmful physical and chemical environmental changes. In crustaceans increased circulating crustacean hyperglycemic hormone (CHH) and hyperglycemia are reported to occur following exposure to several environmental stress. The biogenic amine, serotonin has been found to modulate the CHH levels and oxidation of serotonin into its metabolites is catalysed by monoamine oxidase. The blue swimmer crab, Portunus pelagicus is a dominant intertidal species utilized throughout the indo-pacific region and is a particularly important species of Palk bay. It has high nutritional value and delicious taste and hence their requirements of capture and cultivation of this species are constantly increasing. This species experiences varying and increasing temperature levels as it resides in an higher intertidal zone of Thondi coast. The present study examines the effect of thermal stress on the levels of serotonin and crustacean hyperglycemic hormone in the hemolymph of P. pelagicus and analyzes the effect of the monoamine oxidase inhibitor, pargyline on serotonin and CHH level after thermal stress. The results showed increased levels of glucose, CHH and serotonin on exposure to 26 °C in control animals. Pargyline injected crabs showed highly significant increase in the levels of CHH and serotonin on every 2 °C increase or decrease in temperature. A greater CHH level of 268.86±2.87 fmol/ml and a greater serotonin level of 177.69±10.10 ng/ml was observed at 24 °C. This could be due to the effect of in maintaining the level of serotonin in the hemolymph and preventing its oxidation, which in turn induces hyperglycemia by releasing CHH into hemolymph. Thus, the study demonstrates the effect of thermal stress on the hemolymph metabolites studied and the role of pargyline in elevating the levels of serotonin and CHH on thermal stress in the blue swimmer crab, P. pelagicus .

Recently, lysine-specific demethylase 1 (LSD1) was identified as the first histone demethylase. LSD1 interacted with androgen receptor (AR) and promoted androgen-dependent transcription of target genes, such as PSA, by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9). Meanwhile, the phenomenon of epithelial-mesenchymal transition (EMT) had received considerable attention in tumor recurrence and metastasis. This study examined the effect of Pargyline (an inhibitor of LSD1) on the process of EMT in vitro and in vivo. SCID mice were injected subcutaneously with LNCap cells. Pargyline was given intraperitoneally or not after castration (implemented with Bilateral orchidectomy), then PSA levels in serum and tumor were determined to assess time to androgen-independent progression. The results showed that LSD1 expression was up-regulated when PCa progressed to Castration Resistant Prostate Cancer (CRPC). Pargyline reduced LNCap cells migration and invasion ability, and inhibited the process of EMT by up-regulating expression of E-cadherin, and down-regulating expressions of N-cadherin and Vimentin in vitro and in vivo. Although, Pargyline did not change the level of AR, it reduced PSA expression both in vitro and in vivo. Furthermore, Pargyline delayed prostate cancer transition from androgen-dependent to androgen-independent state (CRPC). These findings indicated that inhibition of LSD1 might be a promise adjunctive therapy with androgen deprivation therapy (ADT) for locally advanced or metastatic prostate cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Methods are presented to tritiate the enzyme inhibitors pargyline and caracemide., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The neurotoxin MPTP is known to induce dopamine release and depletion of ATP in the striatum of rats. Therefore, we studied the changes induced by MPTP and pargyline protection both on striatal dopamine release and on extracellular energy metabolites in freely moving rats, using dual asymmetric-flow microdialysis. A dual microdialysis probe was inserted in the right striatum of rats. MPTP (25mg/kg, 15mg/kg, 10mg/kg) was intraperitoneally administered for three consecutive days. MAO-B inhibitor pargyline (15mg/kg) was systemically administered before neurotoxin administration. The first MPTP dose induced an increase in dialysate dopamine and a decrease of DOPAC levels in striatal dialysate. After the first neurotoxin administration, increases in striatal glucose, lactate, pyruvate, lactate/pyruvate (L/P) and lactate/glucose (L/G) ratios were observed. Subsequent MPTP administrations showed a progressive reduction of dopamine, glucose and pyruvate levels with a concomitant further increase in lactate levels and L/P and L/G ratios. At day 1, pargyline pre-treatment attenuated the MPTP-induced changes in all studied analytes. Starting from day 2, pargyline prevented the depletion of dopamine, glucose and pyruvate while reduced the increase of lactate, L/P ratio and L/G ratio. These in vivo results suggest a pargyline neuroprotection role against the MPTP-induced energetic impairment consequent to mitochondrial damage. This neuroprotective effect was confirmed by TH immunostaining of the substantia nigra., (© 2013 Elsevier B.V. All rights reserved.)

The present study examined dopamine-immunoreactive neuronal structures using immunohistochemistry in conjunction with an anti-dopamine antiserum, following injection of l-3,4-dihydroxyphenylalanine (L-DOPA) with or without an inhibitor of monoamine oxidase (Pargyline) in the cat brain. L-DOPA injection made it possible to detect dopamine immunoreactivity in presumptive serotonergic and noradrenergic cell bodies and axons. Weak to moderate dopamine immunoreactivity was observed in non-aminergic cells (possibly so-called "D" cells containing aromatic L-amino acid decarboxylase (AADC)) in several hypothalamic, midbrain, pontine and medullary nuclei. Intense dopamine immunoreactivity became visible in a large number of cells and axons (possibly containing AADC) with wide distribution in the brain following administration of L-DOPA with Pargyline. AADC is most likely active in cells and axons that take up L-DOPA, where it decarboxylates the L-DOPA to dopamine. However, newly synthesized dopamine in such cells is rapidly oxidized by monoamine oxidase.

The near IR emission at 1270 nm following pulsed laser excitation of methylene blue in deuterium oxide, was used to study the interaction of a singlet molecular oxygen (1O2) with (i) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidation products, and (ii) biosubstrates of relevance in Parkinson's disease. Steady state irradiation of methylene blue and MPTP led to a product with an absorption profile consistent with that of 1-methyl-4-phenyl-2,3-dihydropyridinium ion. This may suggest that even if monoamine oxidase enzyme activity is inhibited by the use of drugs such as Deprenyl and Paragyline the underlying conversion of MPTP to its neurotoxic oxidation product via 1O2 may still take place.

After the loading of incubated, homogeneously innervated tissues with 3H-noradrenaline (monoamine oxidase and catechol-O-methyl transferase inhibited, calcium-containing solution) high K+ released the 3H-amine from adrenergic varicosities. In paired experiments the sensitivity of rat atria to high K+ exceeded that of vasa deferentia. In the rat vas deferens the releasing effect of high K+ was enhanced by drugs or procedures which induce a carrier-mediated outward transport of 3H-noradrenaline, i.e., by ouabain, by glucose deprivation and by hypoxia. In the presence of extracellular calcium desipramine failed to affect the releasing effect of high K+ (except in the absence of glucose or during hypoxia), but in the absence of calcium desipramine reduced it. Apparently, whenever the axoplasmic levels of 3H-noradrenaline are increased, high K+ is able to induce some carrier-mediated outward transport of the 3H-amine. It is suggested that "organ differences" with respect to the sensitivity to high K+ may well be due to hypoxia (plus some lack of glucose) of those varicosities that had been loaded with 3H-noradrenaline. The risk of storage of 3H-noradrenaline in hypoxic varicosities appears to be greater in incubated than in perfused organs, and in the former it is greater in sparsely than in densely innervated tissues.

There are significant discrepancies in the literature concerning the concentration of monoamine oxidase A (MAO A) from a number of tissue sources. Therefore, we compared the two principal techniques that have been used for quantitation of MAO A protein concentration: (1) titration of the enzyme with the MAO A-selective inhibitor clorgyline, and (2) saturation of the enzyme with [3H]-pargyline followed by immunoprecipitation with an MAO A-specific monoclonal antibody. To determine which of the two techniques was likely to yield more reliable values for MAO A, MAO A protein concentrations in the same preparations were determined by quantitative immunoblotting. [3H]Pargyline binding and quantitative immunoblotting yielded comparable values which were markedly lower than those obtained by titration of MAO A with unlabeled clorgyline. Therefore, clorgyline titration can seriously overestimate the concentration of MAO A protein in mitochondrial preparations. Since many literature values for the molecular activity of MAO A have relied upon enzyme concentrations determined by clorgyline binding, we reevaluated the molecular activities of MAO A and B for five important substrates. The ratio, MAO A molecular activity:MAO B molecular activity decreased in the order: serotonin (35:1) greater than tryptamine (12:1) greater than tyramine (3.3:1) greater than dopamine (2.4:1) greater than benzylamine (1:23). No comparable ratio was determined for beta-phenylethylamine because of its previously described substrate inhibition of MAO B, although it is oxidized faster by MAO B over a wide range of concentrations. Comparison of molecular activities and Km values for MAO A and B showed that with the exception of benzylamine and beta-phenylethylamine, MAO A oxidizes the other tested substrates faster than MAO B over a wide range of concentrations. Therefore, measured ratios of MAO A:MAO B activity are generally greater than the ratios of MAO A:MAO B molecules in the preparations.

The dopamine-depleting effects of intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) were studied in young mature (6-8 weeks), older (8-12 months) and aged (18-24 months) mice. No differences were noted between age groups. To rule out the possibility that higher levels of monoamine oxidase (which degrades 6-OHDA) in older animals might be masking an increased sensitivity of older neurons to 6-OHDA, experiments were repeated after treatment with pargyline (50 mg/kg). Again, no differences between age groups were noted. We conclude that aging does not increase the sensitivity of dopaminergic neurons to 6-OHDA.

We have isolated a mouse monoclonal antibody to human platelet monoamine oxidase (MAO) B. The antibody (MAO-1C2) was isolated from a fusion of mouse myeloma P3/X63 Ag8 to spleen cells from a BALB/c mouse immunized with a partially purified platelet preparation in which an estimated 21-31% of the protein was [3H]pargyline-labeled MAO B. The antibody indirectly immunoprecipitates both [3H]pargyline-labeled, catalytically inactive human MAO B, and unlabeled, catalytically active human MAO B. Binding of the antibody to MAO B has no detectable effect on catalytic activity. MAO-1C2 is specific for human MAO B, and fails to immunoprecipitate MAO A indirectly from human placenta or liver. Its ability to immunoprecipitate human MAO B but not MAO A from extracts of human liver provides a convenient technique for separating the two forms of the enzyme for comparative studies. The antibody does not recognize mouse liver MAO B, suggesting that the determinant is not universally expressed on MAO B from all species.

The relative roles of norepinephrine (NE) and dopamine (DA) in sustaining neonatal hyperactivity were assessed in rats given 6-hydroxydopamine (6-OHDA) neonatally into the lateral ventricles after pargyline (P) or desmethylimipramine (DMI) pretreatment. On day 5 after birth, male and female rat pups were pretreated with P (50 mg/kg IP) or DMI (25 mg/kg IP) 30 min before receiving bilateral injections of 6-OHDA (200 micrograms/5 microliters saline containing ascorbic acid 1.0 mg/ml) into the lateral ventricles. Controls were pretreated with P or DMI and then received injections of saline containing the ascorbate. Spontaneous activity was measured in a stabilimeter at ages 30-31, 42-45, 60-63, 75-77, and 120-122 days. Activity in controls and P + 6-OHDA animals was also measured at 254 days of age. The sessions lasted 45 min, except those testing activity in the 254-day-old rats which lasted 12 h. Regional assays of catecholamines carried out when the animals were 150 days old revealed that in the P + 6-OHDA group the levels of NE were reduced in frontal cortex (7% of control levels), caudate (21%), and hippocampus (14%). The NE levels were unchanged or slightly elevated in hypothalamus, ventral midbrain, and pons. The DA levels in the P + 6-OHDA group were depleted in caudate (8%) and ventral midbrain (32%), and unchanged in hypothalamus and pons. In the DMI + 6-OHDA group the NE levels were reduced in caudate (25%) and elevated in hippocampus (188%). The DA levels were depleted in caudate (3%) and ventral midbrain (22%).(ABSTRACT TRUNCATED AT 250 WORDS)

One hr after mianserine administration brain 5-HT concentration was reduced, the greatest decrease was observed with 2.5 mg/kg dose. This reduction lasted for 1 hr. Brain 5-HT turnover was increased by all doses of mianserine used. The increase in brain 5-HT turnover after a single injection lasted for 8 hr. This increase may be related to inhibition of central 5-HT receptors.

Differential normal-pulse voltammetry was combined with treated carbon fibre electrodes for monitoring in vivo extracellular catechols synthesized by noradrenergic terminals innervating the paraventricular hypothalamic nucleus. From urethane-anaesthetized rats, pretreated with a monoamine oxidase inhibitor, pargyline, we were able to monitor a catechol signal which unequivocally corresponded to extracellular noradrenaline, and we observed that ether inhalation for 2 min induced an immediate increase in this signal. Electrical stimulation of the ventral noradrenergic pathway (10 Hz for 40 s) induced a similar effect. On the other hand, from freely moving rats which were not treated with pargyline, we recorded a catechol peak which mainly corresponded to 3,4-dihydroxyphenylacetic acid which was synthesized by noradrenergic terminals. However, electrochemical and biochemical evidence strongly suggested that the increase in this signal induced by a 2-min ether stress does not correspond to 3,4-dihydroxyphenylacetic acid, but to an increase in the extracellular noradrenaline concentration. In both experimental situations the time course of the effects was identical: ether stress induced an immediate and pronounced increase in norepinephrine release, and this effect lasted as long as the stimulus duration. This effect appeared specific for noradrenergic terminals, since no effect on dopamine release was observed when recorded from the striatum or behind the paraventricular hypothalamic nucleus from the A13 dopaminergic group. In conclusion, our data are consistent with those which suggest a facilitatory action of norepinephrine on neurosecretory neurons whose cell bodies are located in the paraventricular hypothalamic nucleus and which play a major role in the hormonal response to stress.

Monoamine oxidase turnover numbers (molecules of substrate converted to product per minute per active site) have been calculated for the human platelet enzyme using [3H]pargyline. Headache patients with high and low monoamine oxidase specific activities relative to controls were found to have turnover numbers very close to those for controls. This finding suggests that their specific activities vary because of differences in the concentration of active monoamine oxidase molecules, rather than differences in the ability of those enzyme molecules to catalyse the deamination reaction.

Striatal amine levels were measured six weeks after unilateral injections of 6-OHDA (8 micrograms) into the substantia nigra in male Wistar rats pretreated with monoamine oxidase inhibitors. After (-) deprenyl.HCl pretreatment (2 mg.kg-1 SC 2hr), beta-phenylethylamine, m- and p-tyramine ipsilateral to the 6-OHDA lesion decreased to 50, 18 and 25% of contralateral levels. DA, DOPAC and HVA also decreased on the lesioned side. Ipsilateral concentrations of tryptamine, 5-HT, 5-HIAA, p-tyrosine and L-tryptophan concentrations were equivalent to contralateral values in this condition. In animals pretreated with pargyline.HCl (200 mg.kg-1 IP 2hr) m- and p-tyramine and tryptamine ipsilateral to the lesion decreased to 48, 59 and 57% of contralateral levels. Ipsilateral DA decreased to 26% of the contralateral value. Under these conditions no change in concentrations of beta-phenylethylamine or of the above acid metabolites or amino acids was observed. The masking of lesion-induced changes in beta-phenylethylamine by pargyline is attributed to the lipophilic nature of of this molecule and consequent diffusion of this amine from other areas after maximal monoamine oxidase inhibition. Conversely the failure to demonstrate lesion-induced changes in tryptamine with (-) deprenyl pretreatment is attributed to the nonselectivity of monoamine oxidase for tryptamine and activity of monoamine oxidase A under these conditions. These results indicate that for further assessment of lesion-induced changes in beta-phenylethylamie and of tryptamine the respective (-) deprenyl and pargyline pretreatments used in this study are appropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

The enzyme monoamine oxidase was labelled in the rat striatum or substantia nigra with locally injected radioactive pargyline. The binding was prevented by a pretreatment with non-radioactive pargyline, or with a combination of clorgyline and deprenyl. Most of the MAO labelled with 3H-pargyline was of the B-type, but also some MAO-A was labelled, as shown in rats pretreated with clorgyline or deprenyl separately. Seven days after the injection of (3H)-pargyline into the striatum a significant labelling was observed in the substantia nigra. This labelling was clorgyline sensitive, indicating type A MAO, and was not present when striatal neurons were destroyed with kainic acid. Labelling of the striatum following 3H-pargyline injection into the substantia nigra was also less in kainate intoxicated striata. Damage of nigral dopamine neurons with 6-hydroxydopamine did not influence the distribution of the label. Thus by using 3H-pargyline, specific labelling and axonal transport of type A MAO in striatal neurons projecting to the substantia nigra was demonstrated.

The turnover of serotonin (5HT) was determined in the raphe area and cortex of mice infected with Pixuna, a strain of intermediate virulence of Venezuelan equine encephalomyelitis virus (VEEV). NMRI-mice, 24 days old, were inoculated intracerebrally (ic) with 300 LD50 of the virus. The animals were sacrificed 4, 7, 15, 21, 30, and 60 days postinoculation. 5HT and 5-hydroxyindoleacetic acid (5HIAA) in raphe and cortex were determined by high performance liquid chromatography (HPLC) with electrochemical detection. Turnover rate of 5HT was determined by the administration of pargyline, p-chlorophenylalanine, and probenecid. The content of 5HT or 5HIAA and 5HT/5HIAA ratios were not significantly different in infected compared with control mice. However, a decrease of 5HT turnover rate, determined after pargyline treatment, was observed in the raphe and not in the cortex of infected mice at 4 and 7 days after the inoculation. The turnover rate/(5HT)0 in raphe is decreased in infected mice with signs of illness, suggesting a lower density of 5HT innervation in this brain area. The administration of p-chlorophenylalanine and probenecid showed that the cortex is also affected, but the synthesis is less modified than metabolism or elimination. Cell bodies of 5HT neurons seem to be more susceptible than projections to infection by Pixuna strain of VEEV.

After the destruction of the noradrenergic ascending pathways, the localization of frontal cortical fields receiving fibers from the dopaminergic mesocortical system has been studied in rats, using a glyoxylic-paraformaldehyde method. The dopaminergic innervation was distributed in two main areas. The area of highest density was a medial field which spread in the medial cortex anterior and dorsal to the genu of the corpus callosum. It did not reach the shoulder region except in the foremost part of the frontal lobe where dopaminergic fibers were scattered in the whole cortex, including the molecular layer. A deep sulcal field was situated between the dorsal bank of the rhinal sulcus and the lateral cortex above it. In addition, a moderately dense band of dopaminergic fibers was observed between the corpus callosum and the anterior commissura, beside the accumbens nucleus. Similar data were obtained with dopamine uptake experiments on reserpine-treated but otherwise normal animals. The frontal areas receiving dopaminergic innervation coincide strikingly with the 'prefrontal cortex' as defined by neuroanatomical studies, which is assumed to be more or less equivalent to the prefrontal cortex of primates and derives direct projections from the amygdala. The functional implications of these findings are discussed.

The localization of the serotonin-like immunoreactive nerves of the rat colon was investigated by means of immunohistochemistry, utilizing an antibody against serotonin. In non-treated colons, serotonin-positive neuropils were consistently detected around the myenteric plexus. In pargyline-treated colons, serotonin-like fibres were demonstrated in association with either the small intramural blood vessels of the submucosa or the extramural nerve bundles. Treatment with 5-hydroxytryptophan (5-HTP) permitted the visualization of additional serotonin-immunoreactive fibres around the large extramural blood vessels. Immunoreactive nerve cell bodies were demonstrated in the myenteric plexus of colons treated with 5-HTP or colchicine. From these observations, it is suggested that the serotoninergic nerves of the rat colon comprise both intrinsic and extrinsic elements.

A defect in the level of monoamine oxidase activity of platelets was observed in essential arterial hypertension. This defect seems dependent upon a lower rate of synthesis of the enzyme and not to the presence of an isoenzyme, as the net rate of return of the enzymatic activity after pargyline inhibition does not significantly differ between hypertensive and normotensive subjects.

The distribution of monoamine oxidase types A and B within the adrenal gland was studied in several mammals by histochemical methods. Controls showed that the methods were valid. The bovine adrenal medulla contained mostly the B type enzyme, distributed heterogeneously, with some A type associated with endothelium, nerves, and cells surrounding the nerves. The bovine adrenal cortex showed a marked zonation of the two types of monoamine oxidase. The zona glomerulosa contained the B type enzyme and the zona fasciculata and zona reticularis contained the type A enzyme. The adrenal medulla of the dog, cat, and rat demonstrated relatively little enzyme activity and it appeared to be both type A and B. The adrenal cortex of these animals appeared to contain mostly the B type enzyme, except the canine zona reticularis, which contained some A type monoamine oxidase as well.

The effect of the monosodium glutamate (MSG) induced lesion of the arcuate nucleus on catecholamines in the arcuate nucleus and median eminence of the mouse hypothalamus was determined using the Falck-Hillarp histofluorescence technique. The number of fluorescent perikarya in the arcuate nucleus of treated animals was decreased approximately 60%; the fluorescence intensity of surviving neurons was notably reduced. These changes were accompanied by a reduction in the intensity of fluorescence in the median eminence. Pretreatment of control and MSG-lesioned animals with a monoamine oxidase inhibitor (pargyline) greatly increased fluroescence in the median eminence and arcuate nucleus of both groups. However, the number of fluorescing perikarya of the arcuate nucleus of the normal pargyline treated group far exceeded that of the pargyline MSG animals. It is concluded that neonatally administered MSG caused destruction of a large number of dopaminergic arcuate perikarya.