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F Dajas

Publications and source records attributed to F Dajas.

At least 37 records · Page 2Linked to original sources
PubMed1994

Monoamine oxidase inhibitory effects of some 4-aminophenethylamine derivatives.

The in vitro and ex vivo monoamine oxidase (MAO) inhibitory effects of (+/-)4-dimethylamino-alpha-methyl-phenethylamine (4-DMAA) and (+/-)4-methylamino-alpha-methyl-phenethylamine (4-MAA) were reassessed, in comparison with the previously unstudied achiral parent compound, 4-dimethyl-aminophenethylamine (4-DMAPEA) and with a salt of 4-DMAA enriched in the levo isomer, ("-")-4-DMAA, using amiflamine [S-(+)-4-dimethylamino-alpha,2-dimethylphenethylamine] as positive control. The in vitro studies confirmed that 4-amino-alpha-methylphenethylamine derivatives are highly selective and reversible MAO-A inhibitors. Furthermore, ("-")-4DMAA was less active than the racemic mixture. The side chain-unsubstituted compound, 4-DMAPEA, proved to be a nonselective and reversible MAO inhibitor. The ex vivo results, in which catecholamines, serotonin (5-HT) and their metabolites were measured in two brain regions after i.p. administration, confirmed the results obtained in vitro. These results are consistent with the suggestion that the 4-amino group contributes to MAO inhibitory effects of alpha-methyl-phenethylamines, and show that the presence and orientation of an alpha-methyl side chain substituent may be important when determining the potency and selectivity of these compounds. All compounds tested could be quantified by HPLC with electrochemical detection.

Animals↗
PubMed1994

4-Dimethylaminophenethylamine, a sensitive, specific, electrochemically detectable monoamine oxidase-B substrate.

4-Dimethylaminophenethylamine (DMAPEA) was characterized as an MAO substrate. This compound was unaffected by MAO-A, while its oxidation by MAO-B was linear as a function of both time and enzyme concentration, with Km = 5.8 microM and Vmax = 21.2 pmol/min/mg protein, using a crude rat brain mitochondrial suspension as source of MAO. Both DMAPEA and its oxidation product, 4-dimethylaminophenylacetic acid (DMAPAA), can be detected electrochemically at 0.85 V. The high MAO-B affinity and selectivity of DMAPEA, together with its low oxidation potential, make this molecule a unique tool to determine MAO-B activity in a wide variety of tissue preparations using HPLC-ED.

Animals↗
PubMed1994

Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea.

The pharmacological effects of 5,7-dihydroxyflavone (chrysin), a naturally occurring monoflavonoid that displaces [3H]flunitrazepam binding to the central benzodiazepine (BDZ) receptors, were examined in mice. In the elevated plus-maze test of anxiety, diazepam (DZ, 0.3-0.6 mg/kg) or chrysin (1 mg/kg) induced increases in the number of entries into the open arms and in the time spent on the open arms, consistent with an anxiolytic action of both compounds. The effects of chrysin on the elevated plus-maze was abolished by pretreatment with the specific BDZ receptor antagonist Ro 15-1788 (3 mg/kg). In the holeboard, diazepam (1 mg/kg) and chrysin (3 mg/kg) increased the time spent head-dipping. In contrast, high doses of DZ (6 mg/kg) but not of chrysin produced a decrease in the number of head dips and in the time spent head-dipping. In the horizontal wire test, diazepam (6 mg/kg) had a myorelaxant action. In contrast, chrysin (0.6-30 mg/kg) produced no effects in this test. These data suggest that chrysin possesses anxiolytic actions without inducing sedation and muscle relaxation. We postulate that this natural monoflavonoid is a partial agonist of the central BDZ receptors.

Animals↗
PubMed1994

Recovery of central noradrenergic neurons one year after the administration of the neurotoxin DSP4.

The long-term effects of the systemic administration of DSP4 (N-(2-chloroethyl)N-ethyl-2-bromobenzylamine hydrochloride), a selective noradrenergic neurotoxin, on the endogenous levels of monoamines and their metabolites and on alpha- and beta-adrenoceptors in selected brain regions of the rat were examined. After 7 days, DSP4 caused a marked reduction (about 80%) of endogenous noradrenaline levels in locus coeruleus-innervated regions. At 90, 240 and 300 days after DSP4 injection, a partial and gradual recovery (50%, 41% and 25% of control values, respectively) of the noradrenaline cortical levels was evident. One year after DSP4 administration, brain regional noradrenaline stores were almost completely recovered. No changes in 5-hydroxytryptamine levels were observed in the three time intervals, but a mild decrease in cortical and hippocampal 5-hydroxyindolacetic acid levels was found 7 days after DSP4 injection. Following the profound noradrenaline depletion seen at 7 days, the cerebral cortical density of alpha 1-, alpha 2- and beta-adrenoceptors was significantly increased. Assessment of adrenergic receptors in cerebral cortex at 365 days after DSP4 injection, indicated that alpha 1- and alpha 2-adrenoceptor densities did not differ from control values; however, the density of beta-adrenoceptors remained increased. No changes were observed in the affinities of the three types of adrenoceptors studied. These results indicate that after a selective noradrenergic denervation induced by DSP4, there is a slow and gradual recovery of noradrenaline stores and of alpha 1- and alpha 2-adrenoceptor populations, suggesting a possible regrowth and/or collateral sprouting of noradrenergic terminals.

Animals↗
PubMed1993

Differential cholinergic and non-cholinergic actions of acetylcholinesterase in the substantia nigra revealed by fasciculin-induced inhibition.

The effects of the peptide fasciculin (FAS), a potent inhibitor of acetylcholinesterase (AChE) have been examined, following unilateral microinfusion, on tissue levels of monoamines in the rat substantia nigra and concomitant circling behaviour. Although FAS inhibited 87% of total AChE, the levels of dopamine and its metabolites remained unchanged. Furthermore, the treatment induced modest contraversive rotation which was markedly enhanced in the presence of a systemic challenge with apomorphine. This behavioural effect of FAS was partially reversed by systemically administered atropine. Any possible interaction of FAS with nigral dopamine systems was further investigated by testing the peptide in animals that five days earlier had undergone a 6-hydroxydopamine (6-OHDA) lesion of the SN such that dopamine and AChE were significantly but not completely reduced. In a majority of these animals, FAS treatment caused a reversal of the lesion induced ipsiversive rotation, ie restored contraversive rotation. It is concluded that in the SN, FAS can have biochemical and behavioural actions independent of local dopamine systems and linked to cholinergic transmission. In addition, treatment with FAS in the substantia nigra also reveals the possible existence of at least two distinct pools of AChE with, respectively, non-cholinergic and cholinergic actions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Hippocampal and entorhinal glucose metabolism in relation to cholinergic theta rhythm.

Hippocampal and entorhinal cortex glucose metabolism were studied by 14C-2-deoxyglucose (2-DG) autoradiography in anesthetized rats with and without continuous theta rhythm (theta). 2-Deoxyglucose changes in specific cytoarchitectonic regions were precisely assessed by n innovative approach. In the absence of theta there were areas with a higher glucose metabolism corresponding to neuropile regions at CA3, dentate gyrus, and subiculum, while the cellular layers always showed lower values. In the presence of theta, provoked by intraventricular injections of anticholinesterases (i.e., physostigmine) or curarimimetics (i.e., d-tubocurarine), 2-DG uptake showed two opposite significant changes in relation to controls: a) it increased in the outer zone of the molecular layer (inner blade) of the dentate gyrus, and in the stratum lacunosum-moleculare of CA3, suggesting an increase in perforant path input during theta rhythm; b) it decreased in the hilar dentate region. This noteworthy decrease in metabolic activity probably reflects an hilar inhibition by local circuits during theta rhythm generation.

Acetylcholine↗
PubMed1992

Different functional pools of acetylcholinesterase induce changes in rat locus coeruleus noradrenaline metabolism.

The effects of acetylcholinesterase (AChE) inhibition in the locus coeruleus (LC) were studied in rats utilizing fasciculin (FAS) and BW248c51 (BW). Both inhibitors were stereotaxically injected into the right LC and the animals were sacrificed 24 h later. Similar groups received atropine (30 mg/kg i.p.) every 5 h during 24 h. Another group of FAS-treated rats received naloxone twice (5 mg/kg i.p.) in 24 h. Other groups of FAS-treated rats were sacrificed 3 and 7 days after injection. An inhibition of 70% of LC AChE activity was observed 24 h after FAS or BW injection. Either FAS or BW induced a significant increase in NA levels in the injected LC compared to control values. Atropine treatment failed to block the FAS effect but it was able to counteract the BW-induced NA increase. NA levels were still increased 3 days after FAS treatment and returned to control values at day 7.

Acetylcholinesterase↗
PubMed1992

Catalepsy induced by striatal acetylcholinesterase inhibition with fasciculin in rats.

The acetylcholinesterase inhibitor peptide fasciculin (FAS) was bilaterally injected into the striatum of rats. Twenty-four hours after injection, animals showed a cataleptic syndrome that was potentiated by haloperidol (HAL). The catalepsy was significantly decreased by IP atropine. Biochemically, only an increase of the homovanillic acid in the striatum was found 24 h and 7 days after FAS treatment. Seven days after the intrastriatal FAS injection, there was no HAL potentiation of catalepsy, which was even lower than that of rats treated with IP HAL after intrastriatal injection of saline. Results are interpreted as showing the central role of the cholinergic system in the induction of catalepsy in the rat.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Two polypeptides from Dendroaspis angusticeps venom selectively inhibit the binding of central muscarinic cholinergic receptor ligands.

Two new polypeptides were isolated and purified from the venom of the snake Dendroaspis angusticeps, which also contains other neuroactive peptides such as Dendrotoxins and Fasciculins. The amino acid composition of the peptides was determined and the first 10 amino acids from the MTX2 N-terminal fragment were sequenced. The so-called muscarinic toxins (MTX1 and MTX2) have been shown to inhibit the specific binding of [3H]QNB (0.15 nM), [3H]PZ (2.5 nM) and [3H]oxoM (2 nM) to bovine cerebral cortex membranes by 60, 88 and 82% respectively. In contrast, they caused only a 30% blockade of the [3H]QNB specific binding to similar membrane preparations from the brainstem. The Hill number for the [3H]PZ binding inhibition by the putative muscarinic toxin MTX2 was 0.95 suggesting homogeneity in the behaviour of the sites involved. The data from [3H]oxoM binding gave a Hill number of 0.83. The decreases in the specific binding involved increases in KD for the three different ligands (8-fold for [3H]QNB, 4-fold for [3H]PZ and 3.5-fold for [3H]oxoM) without significant changes in Bmax, except for a slight decrease in the [3H]oxoM binding sites (-19%); such results suggest that there may be a competitive inhibition between the MTXs and these ligands. The Ki for MTX2/[3H]PZ was 22.58 +/- 3.52 nM; for MTX2/[3H]oxoM, 144.9 +/- 21.07 nM and for MTX2/[3H]QNB, 134.98 +/- 18.35 nM. The labelling of MTX2 with 125I allowed direct demonstration of specific and saturable binding to bovine cerebral cortex synaptosomal membranes. In conclusion, the results reported in this study strongly support the hypotheses that the two polypeptides isolated from D. angusticeps venom selectively inhibit specific ligand binding to central muscarinic receptors, in a competitive manner at least for the antagonist [3H]PZ and that the MTX2 specifically binds to a central site that is suggested to be a muscarinic receptor of the M1 subtype.

Amino Acids↗
PubMed1992

Down regulation of cerebral cortical 3H imipramine binding sites during chronic antidepressant treatment is independent of the central serotonergic innervation.

The effects of chronic antidepressant (AD) administration (amitryptiline 12 mg/Kg i.p., 20 days) on cerebral cortical [3H] imipramine binding sites were examined in control rats and in serotonergic denervated animals. Both treatments independently reduced the density of [3H] imipramine binding sites by 33-40%. Animals submitted to both treatments showed a slightly higher decrease in the Bmax (-50%). No alterations were observed in the apparent dissociation constant. Preincubation of cerebral cortical synaptosomal membranes with Triton X-100 (0.2% v/v), which preferentially dissolves the presynaptic component of the synaptosomes, reduced by 40% the maximal number of [3H] imipramine binding sites in control rats. In chronic AD treated rats or in serotonergic lesioned rats, membranes preincubated with Triton X-100 showed a 30% decrease in the number of [3H] imipramine sites in comparison to the sham group. The combination of both treatments produced an even larger decrease in the density of [3H] imipramine binding sites in Triton X-100 treated membranes (-55%) compared to the sham group. Taken together, these results strongly suggest that cerebral cortical [3H] imipramine binding sites located both pre- and postsynaptically, are down regulated by the long term AD administration independently of the integrity of the central serotonergic system.

5,7-Dihydroxytryptamine↗
PubMed1990

Depletion of the Ca(++)-dependent releasable pool of glutamate in striatal synaptosomes associated with dendrotoxin-induced potassium channel blockade.

The presynaptic actions of the potassium channel blocker Dendrotoxin (DTX) on the Ca+2-dependent release of endogenous glutamate (GLU) and aspartate (ASP) have been tested in synaptosome-enriched preparations from rat striatum. 24 hours after the intrastriatal administration of DTX the K(+)-evoked release of GLU and ASP from the striatal synaptosomes was decreased by 40-45%. No changes in the total synaptosomal content of the amino acids were observed. Superfusion of immobilized synaptosomes with DTX or 4-amino-pyridine resulted in a dose-dependent increase in the basal outflow of GLU and ASP. The release of GLU stimulated by DTX was Ca+2-dependent and was not abolished by superfusing the synaptosomes with 50 microM D-ASP. Moreover, continuous superfusion of DTX (7 microM) to synaptosomes almost completely dumped the subsequent release of GLU and ASP stimulated by 20 mM K+. It is concluded that blockade of presynaptic K+ channels by DTX leads to a massive release of the transmitter pool of GLU (and possible also ASP) from isolated nerve terminals and to a depletion of the amino acid releasable pool.

Animals↗
PubMed1989

Neurochemical and behavioral correlates of unilateral striatal acetylcholinesterase inhibition by fasciculin in rats.

Fasciculin 2 (FAS) an anticholinesterase peptide isolated from the venom of the Green mamba (Dendroaspis angusticeps) was injected into the right striatum of albino rats (1.5 micrograms total amount). The inhibition of acetylcholinesterase (AChE) activity was 86 and 60% 24 h and 7 days after FAS injection, respectively. The treatment with apomorphine (APO) (2 mg/kg s.c.) 24 h after FAS provoked a moderate circling towards the lesioned side that was reverted by atropine (30 mg/kg i.p.). The same dose of APO 7 days after FAS, provoked an inconstant contralateral circling. Neither dopamine nor serotonin nor their metabolites were significantly affected 24 h or 7 days after FAS injection. Radioligand binding assays of dopamine, muscarinic and benzodiazepine receptors only showed a decrease of the density of the muscarinic ones 7 days after FAS. These results are interpreted as showing that the changes provoked by FAS would be compensated but the system would remain in an unsteady state only demonstrable after pharmacological challenge. The chronic down-regulation of muscarinic receptors would compensate the increased cholinergic activity and would therefore block its behavioral expression.

Acetylcholinesterase↗
PubMed1989

Effects of local inhibition of locus coeruleus acetylcholinesterase by fasciculin in rats.

The inhibition of locus coeruleus (LC) acetylcholinesterase (AChE) by Fasciculin II (FAS), a novel anticholinesterase peptide from the green mamba (Dendroaspis angusticeps) venom, was studied in rats. FAS was stereotaxically injected (0.5 microliters of a 1 mg/ml solution) in the right LC. The left LC was taken as control. A group of rats received only saline injected with the same procedure. An inhibition of 80% of LC AChE activity was observed 24 h later. Monoamine and metabolite levels were assessed by high-performance liquid chromatography (HPLC) with electrochemical detection. A significant increase of noradrenaline (NA) levels was found in the injected side when compared with controls 24 h after injection. Neither dopamine, serotonin nor their metabolites or the NA metabolite 4-methoxyhydroxyphenylglycol showed any change after FAS injection. Atropine (30 mg/kg, i.p.) did not prevent the NA increase.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

A double-blind comparative trial of moclobemide v. imipramine and placebo in major depressive episodes.

Patients (n = 490) suffering from a major depressive episode according to DSM-III criteria were randomly allocated to groups receiving either moclobemide, imipramine, or placebo treatment. Subjects were treated as out-patients for 6 weeks. On overall assessment of efficacy and on results of the Hamilton Rating Scale for Depression, both moclobemide and imipramine were superior to placebo, but the differences between moclobemide and imipramine were not significant. Premature termination due to insufficient efficacy was more frequent with placebo than with moclobemide or with imipramine, these differences being significant. The overall assessment of tolerance clearly favoured placebo and moclobemide over imipramine. This was also reflected in the frequency of premature terminations due to poor tolerance, as well as in the frequency of adverse events, which were highest in the imipramine group. The only cardiovascular finding was an increase of the mean heart rate with imipramine, maximum at the end of week 1, while placebo and moclobemide displayed no relevant changes. There were no other important drug-related changes.

Adjustment Disorders↗
PubMed1988

Intrastriatal dendrotoxin injection: behavioral and neurochemical effects.

Unilateral striatal injection of dendrotoxin (DTX), a polypeptide isolated from the venom of the snake Dendroaspis angusticeps, in rats provoked a complex behavioral syndrome characterized by spontaneous circling towards the contralateral side, stereotypic like chewing movements and gnawing, abnormal postures and convulsions. All these symptoms achieved their maximum on the first day, disappearing during the first week after injection. Neurochemical analyses of striatal monoamines and monoamine metabolites showed a significant increase of dopamine and serotonin metabolites 20 hr after DTX injection. A group of animals sacrificed 15 days after toxin administration showed normal levels of monoamines and their metabolites, except for homovanillic acid levels which were still significantly increased. These data indicate that monoamines are involved in the behavioral syndrome elicited by DTX and are possibly related to its excitatory effect upon brain structures in vivo.

Animals↗
PubMed1988

Behavioral and neurochemical effects of intraperitoneally injected dendrotoxin.

Intraperitoneal administration of dendrotoxin, a polypeptide isolated from Dendroaspis angusticeps venom, provoked in mice the appearance of a complex stereotyped behavior including biting, head nodding, 'wet-dog' shakes and rearing. Signs of autonomic hyperactivity as well as hyperreactivity to sound and touch were prominent. Neurochemical analyses of monoamines and monoamine metabolites showed no change 90 min after dendrotoxin, with a decrease in dopamine concentrations and an increase in their metabolites in the striatum starting 3 hr later. Moreover, at this time, dendrotoxin also produced a significant increase of 5-hydroxytryptamine metabolites. These data are interpreted as indicating that dendrotoxin crosses the blood-brain barrier and provokes an increase of the activity at monoaminergic terminals.

Animals↗
PubMed1987

Rat striatal acetylcholinesterase inhibition by fasciculin (a polypeptide from green mamba snake venom).

It has been shown that Fasciculins (FAS), polypeptides isolated from the venom of the green mamba Dendroaspis angusticeps, provoke a powerful inhibition of peripheral acetylcholinesterase (AChE). In the present study, 0.5 microliter of increasing concentrations (10-500 micrograms/ml) of FAS were injected into the striatum of rats. Micropunches taken 2 mm around the injection site showed 90% inhibition of AChE up to 24 h after FAS injection (500 micrograms/ml). AChE activity was about 50% of controls at the 7th day without apparent cell loss. Assessment of AChE activity in the whole striatum showed no inhibition. It is postulated that, due to this potent, localized and long-lasting central nervous system AChE inhibition, FAS could become a useful tool for the study of central cholinergic pathways.

Acetylcholinesterase↗