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PubMed1985

Characterization of mitochondrial monoamine oxidase of Ascaridia galli.

Oxidative deamination of various biogenic monoamines by Ascaridia galli monoamine oxidase (MAO) was blocked by different mammalian MAO inhibitors, namely, iproniazid, trans-PcP, nialamide and pargyline and the blockade was observed to be time as well as concentration dependent. The binding of inhibitors with chick ascarid MAO was of the irreversible type and the nature of the inhibition was competitive. Pargyline showed lowest I50 (8 microM) and Ki (12 microM) values. Chlorgyline and deprenyl at 100 microM concentration inhibited MAO by about 60 and 40% respectively, indicating the presence of both type A and type B MAO in A. galli.

Animals↗

PubMed1979

Monoamine oxidase in adult Hymenolepis diminuta (Cestoda).

A membrane-bound monoamine oxidase (EC 1.4.3.4) was demonstrated in homogenates of Hymenolepis diminuta. The enzyme oxidized a variety of biologically active amines (in decreasing order: dopamine, adrenaline, noradrenaline, tryptamine, tyramine, octopamine), there was, however, no activity with 5-hydroxytryptamine or benzylamine. No diamine oxidase (EC 1.4.3.6.) could be detected in H. diminuta (using histamine, cadaverine or putrescine as substrates). The monoamine oxidase from H. diminuta was not inhibited by azide, hydroxylamine or semicarbazide, but was inhibited by cupferron, alpha-alpha dipyridyl and iodoacetamide, and by the specific monoamine oxidase inhibitors pargyline, nialamide and iproniazid. Several anthelmintics were also found to be inhibitors of monoamine oxidase. The possible roles of monoamine oxidase in H. diminuta are discussed.

Animals↗

PubMedDate not supplied

Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans, monkeys and mice. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up 3H-dopamine. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1999

Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.

1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Animals↗

PubMed1981

Comparison of the contraction produced by various tryptamine analogues on human basilar arterial and rat aortic strips in vitro.

The effect of various closely related analogues of 5-hydroxytryptamine were studied on the human basilar arterial and rat aortic strips in vitro. All analogues (except 5-methoxytryptamine) contracted both preparations producing maximal responses equivalent to that obtained with 5-hydroxytryptamine. Maximum responses to 5-methoxytryptamine were equivalent to and only 60% of the maximum obtained with 5-hydroxytryptamine on human basilar artery and rat aorta, respectively. The order of potency of the analogues on the human basilar artery was different from that obtained on the rat aorta. 5-methyltryptamine, N-methyltryptamine and tryptamine were equipotent on both tissues, whereas 5-hydroxytryptamine and 5-methoxytryptamine were 229 and 296 times more potent, respectively, on the human basilar artery compared to the rat aorta. Both tissues appear to be deficient in monoamine oxidase, since nialamide or iproniazid did not potentiate responses to tryptamine. It is concluded that the receptor type mediating contraction of the human basilar artery to 5-hydroxytryptamine is different from the classical smooth muscle D-receptor.

5-Methoxytryptamine↗

PubMed2000

Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine oxidase inhibition.

A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine (CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5-hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64-04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily for 5 days) were those known to possess anti-stress properties in other animal models. In contrast to the reference substances investigated (nialamide (CAS 51-12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did not exhibit any activity indicative of MAO inhibition. It was concluded that MAO inhibition was not the mechanism primarily responsible for EGb 761's anti-stress activity.

5-Hydroxytryptophan↗

PubMed1989

Hydrazide antidepressants possess novel antileishmanial activity in vitro and in vivo.

The hydrazide monoamine oxidase inhibitor antidepressants possess a novel antiparasitic action against visceral and cutaneous strains of Leishmania. In vitro, phenelzine was the most active compound tested, while in vivo, nialamide was more potent, and was also effective when applied topically to cutaneous lesions. Despite the coincidence of tricyclic antidepressants also possessing antileishmanial activity, the evidence suggests that the antiparasitic action of the hydrazides is unrelated to either monoamine oxidase inhibition or CNS effects.

Animals↗

PubMedDate not supplied

Tne density of adrenergic nerves at various levels in the guinea-pig lung.

1. Gunea-pig tracheal and lung segments were systematically examined for adrenergic nerves using the fluorescence histochemical technique. Fluorescence in nerves was enhanced with alpha-methylnoradrenaline or by pretreating animals with nialamide. 2. There was a progressive decrese in density of fluorescent fibres in airway smooth muscle from the laryngeal end of the trachea, which was densely innervated, to the bronchioles, which contained only occasional fibres. This was despite obvious fluorescence in blood vessels in the lung. 3. It is suggested that, if adrenergic nerves are involved in reflex bronchodilatation in this species, they directly control larger airways and other factors, e.g. non-adrenergic inhibitory nerves, may be important in the control of smaller airways.

Animals↗

PubMed1962

Effect of sympathomimetic amines on the blocking action of guanethidine, bretylium and xylocholine.

Experiments were carried out in which the adrenergic neurone blocking activity of xylocholine, bretylium and guanethidine was studied by the use of the inhibitory responses of the isolated rabbit ileum to lumbar sympathetic nerve stimulation, and the contractions of the nictitating membrane of the anaesthetized cat in response to stimulation of the cervical sympathetic nerves. In both these preparations, after blockade of the effects of sympathetic nerve stimulation had been produced with xylocholine, bretylium or guanethicdine, the sympathomimetic amines, dexamphetamine, mephentermine, hydroxyamphetamine, ephedrine and phenethylamine, reversed the blockade; if these amines were given first, then the adrenergic neurone blocking agents were ineffective. Tyramine and dopamine were effective on the isolated rabbit ileum but not on the cat's nictitating membrane. Effective antagonism of the adrenergic neurone blocking drugs was also shown by some substances which inhibit mono-amine oxidase but only those which in addition possess sympathomimetic effects. Thus phenelzine, pheniprazine and tranylcypromine were effective whereas iproniazid and nialamide were not. Since xylocholine, bretylium and guanethidine were all antagonized by the same agents, it seems likely that they all produce sympathetic blockade by a similar mechanism. The possibility is discussed that the sympathomimetic amines which antagonize the adrenergic neurone blocking drugs are competing with these substances for the same receptor sites.

Amidines↗

PubMed1976

Extra-vesicular binding of noradrenaline and guanethidine in the adrenergic neurones of the rat heart: a proposed site of action of adrenergic neurone blocking agents.

1 The binding and efflux characteristics of [14C]-guanethidine and [3H]-noradrenaline were studied in heart slices from rats which were pretreated with reserpine and nialamide. 2 Binding of both compounds occurred at extra-vesicular sites within the adrenergic neurone. After a brief period of rapid washout, the efflux of [14C]-guanethidine and [3H]-noradrenaline proceeded at a steady rate. The efflux of both compounds appeared to occur from a single intraneuronal compartment. 3 (+)-Amphetamine accelerated the efflux of [14C]-noradrenaline; this effect was inhibited by desipramine. 4 Unlabelled guanethidine and amantadine also increased the efflux of labelled compounds. Cocaine in high concentrations increased slightly the efflux of [14C]-guanethidine but not that of [3H]-noradrenaline. 5 Heart slices labelled with [3H]-noradrenaline became refractory to successive exposures to releasing agents although an appreciable amount of labelled compound was still present in in these slices. 6 It is suggested that [14C]-guanethidine and [3H]-noradrenaline are bound at a common extravesicular site within the adrenergic neurone. Binding of guanethidine to the extra-vesicular site may be relevant to its pharmacological action, i.e., the blockade of adrenergic transmission.

Amphetamine↗

PubMed1984

Release of endogenous 5-hydroxytryptamine from the myenteric plexus of the guinea-pig isolated small intestine.

The presence of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in, and the release of these substances from, the myenteric plexus-longitudinal muscle (MPLM) layer of the guinea-pig isolated small intestine were investigated. 5-HT and 5-HIAA were measured by high performance liquid chromatography and electrochemical detection. Freshly prepared MPLM contained measurable amounts of 5-HT and 5-HIAA. For the release experiments, the MPLM was incubated in a medium containing the 5-HT uptake inhibitor fluoxetine and the monoamine oxidase inhibitor nialamide; this led to a decrease in the 5-HIAA content of the MPLM whereas the 5-HT content remained unchanged. There was a spontaneous release of 5-HT and 5-HIAA from the MPLM. The release of 5-HT was so small that it was just detectable; it seemed equivalent to about 0.8% of the tissue stores released per min. Depolarization of the tissue by increasing the [K+] or by exposing it to veratridine enhanced the release of 5-HT in a Ca2+-dependent manner whereas the release of 5-HIAA was not increased. Tetrodotoxin inhibited the veratridine-evoked release of 5-HT but did not affect the K+-evoked release of 5-HT. The presence of 5-HT in myenteric neurones and the characteristics of the release of 5-HT from these neurones strongly support the hypothesis that 5-HT is an enteric neurotransmitter.

Animals↗

PubMed1984

The antidyskinetic action of dihomo-gamma-linolenic acid in the rodent.

The antidyskinetic action of dihomo-gamma-linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea-pig by dopamine injected into the striatum (200 micrograms bilateral 2 h after nialamide, 75 mg kg-1, i.p.) and in the guinea-pig and rat by 2-di-n-propylamino-5, 6-dihydroxytetralin (tetralin), 0.025 mg kg-1, s.c. Dopamine and tetralin-induced dyskinesias in the guinea-pig were reduced or abolished by DHLA given i.p., 30-100 mg kg-1, given once daily for 5-10 days. Tetralin-induced dyskinesias were antagonized by DHLA given orally to the guinea-pig (50-200 mg kg-1, 5 days) or in the diet to the rat (approximately 200 mg kg-1 daily for 10-14 days). DHLA injected into the striatum (2.5-20 micrograms bilateral, 2-4 days) also antagonized tetralin-induced dyskinesias in the rat. The antidyskinetic action of DHLA given i.p. to the guinea-pig could be antagonized by aspirin or eicosa-5,8,11,14-tetraynoic acid (100 mg kg-1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25-100 mg kg-1, i.p.) dose-dependently antagonized the antidyskinetic activity of 5 and 20 micrograms DHLA given bilaterally into the striatum (2 days). DHLA (100 mg kg-1 i.p.) given daily for 10 days or approximately 200 mg kg-1 DHLA (daily for 10-14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg-1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg-1 i.p. 7 It is suggested that the selective inhibition of dyskinesias in the rodent by DHLA may reflect a striatal effect with a dependency on conversion to prostaglandins.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1981

Peripheral control of the cat's step cycle. I. Phase dependent effects of ramp-movements of the hip during "fictive locomotion".

Acute spinal and curarized cats can generate "fictive locomotor activity" after an i.v. injection of Nialamid followed by 4-AP and L-DOPA. The efferent burst activity to flexors and extensors can be recorded in peripheral nerve filaments. Ramp-formed movements were applied in the hip at constant angular velocity in different phases of the spontaneous efferent burst activity. The cycle duration was markedly influenced. A flexion or an extension ramp applied in the early part of the "step-cycle" (during flexor activity) will prolong the cycle duration, but in the later part of the cycle instead a marked shortening effect will occur. The transition from a prolongation to a shortening is very steep for the extensive-ramps, with a subsequent gradual increase from a shortening to a lengthening of the cycle. This type of phase response curve expresses a potent peripheral modulatory effect on the central pattern generator. A ramp movement (flexion or extension) applied in the beginning of the flexor burst will reinforce the flexor activity. In the end of the flexor burst instead there is a directional sensitivity with positive feedback, resulting in an excitation of the flexor activity for flexion ramps, but a depression of the flexor activity for extension-ramps. Extension-ramps also show a position dependent effect which enhances the response in the flexors for more extended hip positions.

Animals↗

PubMed1966

An electrophysiological study of 5-hydroxytryptamine receptors of neurones in the molluscan nervous system.

1. 5-Hydroxytryptamine (5-HT) has been iontophoretically applied to the membrane of central neurones of Cryptomphallus aspersa; CILDA neurones (cells with inhibition of long duration) (Gerschenfeld & Tauc, 1964) are the only cells sensitive to 5-HT. The responses to 5-HT is always a depolarization. The CILDA cells studied were also depolarized by ACh.2. From experiments in which pulses of 5-HT and ACh were applied from a double-barrelled micropipette to the CILDA cell soma, it has been calculated that 5-HT and ACh receptors were located at different distances from the injecting micropipette tip. It has also been calculated from the diffusion equation that in the same CILDA cell a 5-HT concentration of 8.2 x 10(-9)M and a ACh concentration of 1.3 x 10(-8)M caused a similar peak depolarization.3. CILDA neurones show ;anomalous' rectification. 5-HT increases the membrane conductance of CILDA.4. 5-HT receptors of CILDA neurone are desensitized by repeated application of 5-HT. The desensitization lasts for ca. 40 sec.5. 5-HT receptors are blocked by lysergic acid diethylamide and its derivatives. Morphine chlorhydrate blocks them non-competitively.6. Some inhibitors of monoamine oxidase (trancylpromine, isocarboxazide, iproniazide and nialamide) have been tested. They do not prolong the action of 5-HT, but block the 5-HT receptors.7. No crossed desensitization between 5-HT and ACh has been observed. Atropine blocks both ACh-receptors and 5-HT receptors, 5-HT receptors appear to be blocked to a greater extent.8. The data presented support the assumption of a excitatory transmitter role of 5-HT to CILDA neurones, but further evidence is necessary to confirm this hypothesis.

Acetylcholine↗

PubMed1973

Release of transmitters into the perfused third cerebral ventrical of the cat.

1. The third cerebral ventricle of cats treated with nialamide and anaesthetized with chloralose was perfused, and the effluent was tested for 5-hydroxytryptamine (5-HT) and also for acetylcholine (ACh) when the perfusion fluid contained neostigmine.2. Under ;resting' conditions a 25 min sample of effluent contained from < 1 to 6 ng 5-HT; the release remained steady during many hours of perfusion. It was necessary to watch out for traces of blood which might contribute to the 5-HT content and which were only visible after centrifugation.3. A number of regions in the ventral mid-brain and hind-brain were stimulated, including the two most anterior nuclei of the raphe, nucleus linearis rostralis and intermedius. Release of 5-HT (rarely more than 2 ng) was only obtained on stimulation of these two nuclei, whereas ACh was released by stimulating many points, such as the reticular formation or the decussation of the superior cerebellar peduncles, but not the two raphe nuclei.4. Low frequencies of stimulation were more effective at releasing 5-HT, and high frequencies at releasing ACh.5. Since the amount of 5-HT released on stimulation was rarely more than 2 ng, a powerful re-uptake process was suspected and confirmed by the use of chlorimipramine. Intravenous, intraperitoneal and intraventricular use of this drug temporarily increased the basal release to values ranging from 20 to 50 ng in 25 min samples, and about trebled the release on stimulation of either of the linear nuclei.6. Intravenous administration of chlorimipramine (10 mg/kg) caused the disappearance of electrical responses evoked in the brain stem by afferent sensory stimuli.

Acetylcholine↗

PubMed2005

Organization of common synaptic drive to motoneurones during fictive locomotion in the spinal cat.

The basic locomotor rhythm in the cat is generated by a neuronal network in the spinal cord. The exact organization of this network and its drive to the spinal motoneurones is unknown. The purpose of the present study was to use time (cumulant density) and frequency domain (coherence) analysis to examine the organization of the last order drive to motoneurones during fictive locomotion (evoked by application of nialamide and dihydroxyphenylalanine (DOPA)) in the spinal cat. In all cats, narrow central synchronization peaks (half-width < 3 ms) were observed in cumulants estimated between electroneurograms (ENGs) of close synergists, but not between nerves belonging to muscles acting on different joints or to antagonistic muscles. Coherence was not observed at frequencies above 100 Hz and was mainly observed between synergists. Intracellular recording was obtained from a population of 70 lumbar motoneurones. Significant short-term synchronization was observed between the individual intracellular recordings and the ENGs recorded from nerves of the same pool and of close synergists. Recordings from 34 pairs of motoneurones (10 pairs belonged to the same motor pool, 11 pairs to close synergists and 13 pairs to antagonistic pools) failed to reveal any short-lasting synchronization. These data demonstrate that short-term synchronization during fictive locomotion is relatively weak and is restricted to close synergists. In addition, coherence analysis failed to identify any specific rhythmic component in the locomotor drive that could be associated with this synchronization. These results resemble findings obtained during human treadmill walking and imply that the spinal interneurones participating in the generation of the locomotor rhythm are themselves weakly synchronized. The restricted synchronization within the locomotor drive to motoneuronal pools may be a feature of the locomotor generating networks that is related to the ability of these networks to produce highly adaptive patterns of muscle activity during locomotion.

Adaptation, Physiological↗

PubMed1981

Stimulus--response relationships during locomotion.

Crossed hind limb responses to high intensity stimulation of the superficial peroneal nerve in the cat were studied under various conditions. In precollicularly decerebrate cats walking on a treadmill, the same stimulus train evokes a crossed extension response during the contralateral stance phase and a crossed flexion response during the contralateral swing phase. In acute spinal cats (Th 13) injected with clonidine, a similar stimulus train can evoke a crossed extension response when the limb is manually placed in flexion and a crossed flexion response when the limb is positioned in extension. During "fictive" locomotion, induced in spinal paralyzed cats by nialamide an L-DOPA, the same stimulus may increase the amplitude and (or) the duration of crossed flexor or crossed extensor activity (in-phase responses). In some instances in these preparations, the crossed responses may be out-of-phase with the central rhythm. It is concluded that crossed hind limb responses during locomotion are selected by both central and peripheral mechanisms.

Animals↗

PubMed1988

Rhythmic fluctuations of dorsal root potentials and antidromic discharges of primary afferents during fictive locomotion in the cat.

1. This study examines rhythmical activity of primary afferents occurring during "fictive" locomotion in decorticate paralyzed cats. Oscillations of the dorsal root potential (DRP) at the frequency of the locomotor rhythm have been observed at the lumbosacral and cervical levels. In addition, rhythmic antidromic discharges of primary afferent units have been recorded from the proximal stumps of cut dorsal root filaments. A detailed study of the relationships between the DRP fluctuations, the antidromic discharges, and the locomotor activity monitored by recording extensor and flexor muscle nerves is presented. 2. Typical DRP recordings from both lumbosacral and cervical levels show two negative waves (N1 and N2) separated by positive troughs (P1 and P2) in each locomotor cycle. Linear regression analyses indicate that the first negative wave (which generally has the largest amplitude) is related to the flexor activity whereas the second is related to the extensor activity. The relative amplitude of the two negative waves may vary without apparent concomitant changes in the recorded flexor or extensor motor nerves. The positive troughs occur respectively close to the period of transition between flexor and extensor activities and between extensor and flexor activities. 3. DRPs of similar period and amplitude can be observed in different ipsilateral roots recorded simultaneously. The DRPs recorded bilaterally from the same segment have the same periodicity but are out-of-phase. Point-to-point variations of amplitude in bilaterally recorded roots are not correlated. This suggests that the polarization of primary afferents on one side is mainly related to the locomotor events on that side. DRPs have been recorded in cats spinalized at Th13 and injected with nialamide and l-DOPA. This suggests that although the supraspinal contribution may be important, at least part of the DRPs may result from locomotor activity within the spinal cord itself. 4. A salient finding in our experiments was that of rhythmic antidromic unit discharges in the proximal stump of cut dorsal root filaments. Of the 194 units recorded, 19% (37/194) discharged in distinct bursts occurring at fixed times in the locomotor cycle. The majority of the units discharged either one burst during the period of flexor or extensor activity or one burst during one of the two periods of transition. Three units discharged two bursts per locomotor cycle. The frequency of the antidromic discharges of some units in one limb were also found to be modulated by stimulation of the skin or passive manipulation of the limbs.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗