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Biomedical subjects

G Jaim-Etcheverry

Publications and source records attributed to G Jaim-Etcheverry.

At least 19 recordsLinked to original sources
PubMed1988

[N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) increases the liberation of 3H-noradrenaline produced by depolarization of the nerve ending].

When injected systemically to rodents, DSP4 inhibits the uptake of noradrenaline (NA) and depletes endogenous NA levels in the central nervous system and in the periphery. Pretreatment with the NA uptake blocker desipramine (DMI), with the NA precursor l-dopa or with the MAD inhibitor, pargyline, prevents the toxic effects of the compound. To investigate the mechanism of the NA depleting action of DSP4, the release of the neurotransmitter induced by nerve stimulation was studied "in vitro" in a tissue sensitive to the neurotoxic action of DSP4 such as the rat cerebral cortex previously loaded with tritiated NA. Incubation with 10 mumol/l DSP4 increased the spontaneous release of tritium from the cortex and produced a two-fold enhancement of tritium outflow during the stimulation of the cortical slices by exposure to K+ 20 mmol/l for 1 m. When the experiments were performed in a Ca++ free medium, DSP4 increased the spontaneous tritium outflow, but did not enhance the NA release by depolarization with K+. This latter effect could be due to the interaction with alpha-adrenoceptors since DSP4 did not potentiate the action of the alpha-antagonist yohimbine (1 mumol/l). DSP4, as did other uptake blockers, reduced the inhibitory effect of clonidine (0.1 mumol/l) on the NA release. Clonidine pretreatment "in vivo" (2 mg/kg), did not counteract the effect of DSP4 (25 mg/kg), suggesting that the enhanced release of NA induced by K+ does not play an important role in the depletion caused by DSP4. This is supported by the fact that DSP4 also enhanced the release of NA evoked by field stimulation of the rat vas deferens, a tissue resistant to the NA depleting action of the compound. The results indicate that the enhancement of the stimulation-induced release caused by DSP4, does not seem to play a triggering role in the NA depletion caused by the compound.

Animals↗
PubMed1987

The aziridinium derivative of DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) accelerates the beating rate of isolated rat atria by enhancing the spontaneous release of noradrenaline.

The aziridinium derivative of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (az-DSP4) depletes endogenous noradrenaline stores and exerts neurotoxic actions on noradrenergic neurons. These effects are persistent in the central nervous system and transient in the periphery. To determine if transmitter release plays a role in the noradrenaline depletion caused by az-DSP4, the action of the compound was studied in isolated and spontaneously beating rat atria. 1. az-DSP4 enhanced atrial beating rate when present in the incubation medium at concentrations ranging from 10(-7) M to 10(-4) M but at 10(-3) M decreased that rate below basal levels. 2. Preincubation of atria for 30 min with the noradrenaline uptake blocker desimipramine (DMI, 10(-6) M) or with the beta-blocker propranolol (10(-7) M), abolished the positive chronotropic action of az-DSP4. 3. The rate-accelerating effect of az-DSP4 could be prevented by pretreating the rats with reserpine (5 mg/kg i.p. 24 h) or enhanced by pargyline pretreatment (100 mg/kg i.p. 18 h). 4. az-DSP4 stimulated the spontaneous efflux of tritium from the isolated atria previously labeled with 3H-noradrenaline (4 X 10(-7) M), an increase that was mainly accounted for by DOPEG. 5. COMT and MAO activities in atria homogenates were inhibited by az-DSP4 in a concentration-dependent manner. However, MAO inhibition did not result in a change of the metabolic pattern as could be expected. 6. The results obtained indicate that az-DSP4 enhances the rate of spontaneous beating of isolated rat atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of [3H]norepinephrine from rat cortical slices.

The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with [3H]NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

Amines↗
PubMed1983

Different effects of neonatal vinblastine on peripheral and central noradrenaline neurons.

The systemic injection of newborn rats of the mitotic inhibitor vinblastine sulfate (0.25 microgram/s.c. 48 h after birth), produces marked and persistent changes in peripheral sympathetic neurons. Approximately half the neuronal population of the superior cervical ganglia was destroyed already at 16 days of age and this was accompanied by a partial but persistent depletion of noradrenaline (NA) from peripheral organs receiving a rich sympathetic nerve supply such as the heart, salivary glands and spleen. After the systemic injection of vinblastine to newborn rats, the content of NA in several brain regions remained unaltered at 45-60 days of age. To overcome the obstacle that the blood-brain barrier could represent to vinblastine penetration into the brain, the compound was injected directly into the brain of rat pups at 2 days of age (0.25-1.0 microgram). When these animals were killed 45-60 days later, no changes were found in the concentration of NA in the cerebral cortex, the spinal cord or the cerebellum but NA levels were increased in the brain stem. Besides producing a partial but persistent peripheral sympathectomy, vinblastine injected either systemically or intracerebrally to newborn rats, provides a useful tool for the analysis of similarities and differences between the ontogenesis of central and peripheral NA neurons.

Animals↗
PubMed1983

Ultrastructural evidence for monoamine uptake by vesicles of pineal sympathetic nerves immediately after their stimulation.

Bilateral electrical stimulation of the preganglionic fibers to the superior cervical ganglia of the rat markedly reduces the number of osmiophilic dense cores present in the nerve vesicles of the sympathetic fibers in the pineal gland. These cores owe their density to the presence of noradrenaline and serotonin in the vesicles. When sympathetic nerves of the pineal organ are exposed immediately after stimulation for a brief period to the false neurotransmitter 5-hydroxydopamine, either in vitro or in vivo, dense precipitates reappear in the electron-lucent vesicles. On the basis of these observations, it is concluded that the vesicles remaining in the nerves after releasing their neurotransmitter content have the capacity to take up and store monoamines. This provides a morphological correlate for the recent biochemical evidence suggesting that the vesicles in sympathetic nerves are reused after neurotransmitter release.

Animals↗
PubMed1980

Antiserum to nerve growth factor does not prevent the increase of brain stem noradrenaline after neonatal 6-hydroxydopa.

Antiserum to nerve growth factor (anti-NGF) given intraventricularly to newborn rats systemically injected with 6-hydroxydopa (6-OH-DOPA), did not prevent the long-term increase of brain stem noradrenaline produced by 6-OH-DOPA when given alone. Since the anti-NGF was biologically active and penetrated into the brain parenchyma, the role played by NGF in the outgrowth of central noradrenergic neurons, responsible for the elevation of brain stem noradrenaline, does not seem to be important.

Animals↗
PubMed1980

DSP-4: a novel compound with neurotoxic effects on noradrenergic neurons of adult and developing rats.

The pharmacological actions of the compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) are compatible with a specific neurotoxic effect on both peripheral and central noradrenergic neurons. The systemic injection of DSP-4 to adult rats transiently alters sympathetic neurons in the periphery but in the central nervous system the compound determines a marked and prolonged reduction of noradrenaline (NA) levels in all brain regions studied. When DSP-4 was injected systemically to rats at birth in doses ranging from 6.25 to 100 micrograms/g, no changes were found in peripheral sympathetic neurons 40 days later. On the contrary, in the same conditions and in relation to the dose injected, there were marked and persistent changes in the levels of NA in different regions of the brain. In the cerebral cortex and the spinal cord, the neonatal injection of SDP-4 produced a marked and long-lasting depletion of NA levels, similar to that observed after injection of the compound to adult rats. These changes were accompanied by a moderate increase in brain stem NA and a marked elevation of the amine in the cerebellum. These changes, different from the depletion observed in both regions when the compound was given to adult rats, are however similar to those observed after the neonatal injection of the neurotoxic compounds 6-hydroxydopamine or its precursor amino acid, 6-hydroxydopa. This indicates that probably central noradrenergic neurons respond in the same manner after different chemical injuries. DSP-4 crosses the placental barrier because when it was given to pregnant rats at the end of gestation, long-term changes were found in brain NA levels in their offspring, similar to those produced by the neonatal administration of the compound. This new neurotoxic compound provides a very useful tool for the study of noradrenergic neurons both in adult animals and during ontogenesis.

Age Factors↗
PubMed1977

Differential effect of various 6-hydroxydopa treatments on the development of central and peripheral noradrenergic neurons.

6-Hydroxydopamine or 6-hydroxydopa injected systemically into newborn rats produced marked changes in the development of central and peripheral noradrenergic neurons. Noradrenaline concentration was elevated in the brain stem, particularly in the pons, and decreased in the cerebral cortex and the spinal cord while in the cerebellum, the effects were dependent on the mode of administration. The changes produced by 6-hydroxydopa in brain regional noradrenaline were related to the dose injected at birth. Similar modifications in the development of central noradrenergic neurons were found in the offspring of rats which had received 6-hydroxydopa at 16 days of gestation. The involvement of peripheral sympathetic neurons varied with the compound used and the form of its administration. Thus, 6-hydroxydopamine produced a permanent although partial peripheral sympathectomy, an effect which was less evident following multiple injections of 6-hydroxydopa after birth and almost minimal after a single injection. The prenatal administration of 6-hydroxydopa did not alter peripheral sympathetic neurons. It is concluded that with the appropriate treatment schedule, it is possible to lesion selectively the noradrenergic neurons in the central nervous system.

Animals↗
PubMed1975

6-hydroxydopa during development of central adrenergic neurons produces different long-term changes in rat brain noradrenaline.

6-hydroxydopa (6-OH-DOPA) administered to rats during their early development produces long-term modifications in the content of brain noradrenaline (NA) which have regional differences. An increase in brain stem NA is observed when the rats are exposed to the drug between the day 14 of gestation and the 9th postnatal day. When 6-OH-DOPA is injected subcutaneously on the 13th postnatal day or later, there is a decrease in brain stem NA. On the other hand, the content of NA in the telediencephalon is depleted for the first time in rats exposed to the drug during the day 16 of gestation, the decrease is more evident when the injection is done on days 17 or 18 and the effect is also marked when the drug is administered in the period between the day of birth and the 20th day of age. These results indicate that 6-OH-DOPA exerts different effects during the process of development and that the increase in brain stem NA is not solely dependent on the depletion produced in the forebrain because both phenomena are temporally dissociated. The adrenergic neurons injured by the drug, most probably respond in such a way that leads to an increase in brain stem NA only during the period in which they are under the influence of the factors controlling their physiologic development.

Animals↗