PubMed Health⌕ Search

Biomedical subjects

B Scatton

Publications and source records attributed to B Scatton.

At least 19 recordsLinked to original sources
PubMed1992

Neurotoxic effects of the intrastriatal injection of spermine and spermidine: lack of involvement of NMDA receptors.

The injection into the rat striatum of the polyamines spermine and spermidine (30-300 nmol) produced, 1 week after injection, a dose related loss of the neuronal markers glutamate decarboxylase and choline acetyltransferase and a decrease in the density of N-methyl-D-aspartate (NMDA) receptors (as labelled with [3H]TCP). In parallel, an increase in peripheral type benzodiazepine (p) binding site density (a marker of the associated glial reaction and macrophage invasion) was observed. Intrastriatal injection of putrescine (300 nmol) did not significantly alter any of these markers. The effect of spermine on these neuronal and glial markers was maximal 3 days after injection, and tended towards control levels at 16 days post injection. The neurotoxic effects of spermine were confirmed by histological analysis demonstrating a massive neuronal loss around the injection site and an accumulation of astrocytes and phagocytes. The neurotoxic effects of spermine (250 nmol) were not antagonised by the previous administration of the NMDA receptor antagonist MK-801 (10 mg/kg, i.p.). Thus polyamine neurotoxicity in vivo does not seem to involve NMDA receptor activation, although it may possibly be related to the multiple effects of these compounds on diverse calcium channels and processes regulating calcium homoeostasis.

Animals↗
PubMed1992

Lack of neuroprotective effect of some sigma ligands in a model of focal cerebral ischemia in the mouse.

The potential neuroprotective effect of seven sigma ligands has been evaluated in a mouse model of focal cerebral ischemia (induced by coagulation of the left middle cerebral artery) and compared to that of known N-methyl-D-aspartate (NMDA) antagonists. When given after the induction of cerebral ischemia, the NMDA receptor antagonists dizocilpine and CGS 19755 and the mixed NMDA antagonist/sigma ligand eliprodil (SL 82.0715) afforded very substantial protection against cortical infarction (92, 44 and 72%, at the doses of 1, 10 and 10 mg/kg, i.p., for dizocilpine, CGS 19755 and eliprodil, respectively). In contrast, none of the sigma ligands investigated--DTG, DMTG, GBR 12909, (+)- and (-)-3-PPP (up to 10 mg/kg), BMY 14802 (up to 30 mg/kg), except haloperidol at a high dose (3 mg/kg)--had neuroprotective effects.

Animals↗
PubMed1992

SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons.

In the present study, we have examined by light and electron microscopy whether SL 82.0715, a polyamine site-directed N-methyl-D-aspartate (NMDA) antagonist, causes pathological changes in cerebrocortical neurons similar to those observed with NMDA receptor channel blockers in the rat brain. Dizocilpine (1, 2 and 5 mg.kg-1, s.c.) induced a dose-dependent vacuolization of the neuronal cytoplasm in specific neurons of the retrosplenial and posterior cingulate cortices (layers III and IV) even at the lowest dose studied, at 6 h post-injection. In contrast, SL 82.0715 (10 and 30 mg.kg-1 i.p., 6 h post-injection) did not induce such morphological alterations. These results indicate that NMDA receptor blockade is not necessarily associated with alterations of cortical neuronal morphology.

Animals↗
PubMed1992

Effect of local injection of 8-OH-DPAT into the dorsal or median raphe nuclei on extracellular levels of serotonin in serotonergic projection areas in the rat brain.

Using in vivo microdialysis, we have examined the effects of local administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into either the dorsal (DRN) or the median (MRN) raphe nucleus on extracellular levels of serotonin (5-HT) in the corresponding projection fields, namely striatum and ventral hippocampus in the anaesthetized rat. Local injection of 8-OH-DPAT (0.5 microgram/0.1 microliter) in the DRN reduced extracellular 5-HT levels in the striatum (-55%) and to a lesser extent in the hippocampus (-22%). When injected at the same dose in the MRN, 8-OH-DPAT caused a marked decrease in 5-HT output in the hippocampus (-41%) and had no effect in the striatum. Autoradiographic studies performed on brains from animals that received a local injection of [8H]8-OH-DPAT into either the DRN or MRN under similar experimental conditions indicated that the radioactivity remained localized within each midbrain raphe nucleus. These results confirm anatomical data demonstrating that the striatum and the ventral hippocampus receive their serotonergic innervation preferentially from the DRN and the MRN, respectively.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

5-HT1C receptors mediate phosphoinositide turnover activation in the immature rat hippocampus.

The activation of phosphoinositide turnover in rat cerebral cortex and choroid plexus is triggered by the stimulation of 5-HT2 and 5-HT1C receptors, respectively. To characterize the 5-HT receptor subtype mediating the activation of phosphoinositide turnover in the hippocampus, the potency of several 5-HT agonists and antagonists on total [3H]inositol phosphate formation has been compared in the hippocampus, cerebral cortex and choroid plexus of immature rats. 5-HT, alpha-methyl-5-HT, quipazine, MK-212, mCPP (m-chlorophenylpiperazine) and TFMPP (m-trifluoromethylphenylpiperazine) are less potent and efficient in stimulating phosphoinositide turnover in the hippocampus and cerebral cortex than in the choroid plexus. However, for a number of 5-HT receptor antagonists (ketanserin, spiperone, ritanserin, pizotifen, cyproheptadine, mesulergine, mianserin, methiothepin, methysergide) there is a good correlation (r = 0.82) between their antagonistic potency in the hippocampus and choroid plexus while such correlation is not observed for the hippocampus and cerebral cortex. The specific 5-HT2 receptor antagonist spiperone only partially antagonizes (37% inhibition at 1 microM) the stimulation by 5-HT of phosphoinositide turnover in the hippocampus. These results suggest that in the immature rat hippocampus the activation of phosphoinositide turnover by 5-HT is mainly mediated by the 5-HT1C receptor subtype.

Animals↗
PubMed1992

Increase in omega 3 (peripheral-type benzodiazepine) binding site densities in different types of human brain tumours. A quantitative autoradiography study.

The density of omega 3 (peripheral type benzodiazepine) binding sites, a marker of reactive and tumoural cells, has been measured in different types of human brain tumours; omega 3 sites were quantified autoradiographically in sections from biopsy or autopsy specimens labelled with the specific radioligand 3H-PK 11195. Compared to normal brain parenchyma, up to 12-fold increase in omega 3 site densities were found in apparently viable areas of high grade astrocytoma and glioblastoma specimens, whereas more limited increases (2 to 3-fold) in this marker were observed in areas of necrosis. Low grade gliomas (astrocytomas) and meningiomas exhibited only moderate increases (2 to 3-fold) in this autoradiographic marker. Metastases of lung or kidney origin were characterized by greatly elevated (up to 20-fold) omega 3 site densities as compared to normal brain parenchyma. In every case, there was a good spatial correspondence between the histopathological limits of the tumour and the anatomical location of the increase in omega 3 site densities. These results suggest that omega 3 site densities in human brain tumours reflect their proliferative activity and point to a possible future usefulness of positron or gamma-ray emitting omega 3 site ligands for the clinical investigation and detection of human brain proliferative diseases.

Astrocytoma↗
PubMed1992

Implication of the polyamines in the neurotoxic effects of N-methyl-D-aspartate.

N-Methyl-D-aspartate (NMDA) receptor activation selectively releases the polyamines spermine and spermidine from the rat striatum in vivo. The intrastriatal injection of spermine or spermidine is neurotoxic, but this toxicity is not blocked by MK-801 and unlikely to be mediated via the NMDA receptor. The neurotoxic effects of intrastriatally injected NMDA can, however, be reduced by polyamine synthesis inhibition with difluoromethylornithine. Alterations in polyamine metabolism in the ischaemic brain, although perhaps induced by NMDA receptor activation, may contribute to ischaemic cell loss via NMDA-independent mechanisms, possibly related to the diverse effects of polyamines on calcium homoeostasis and channel function.

Animals↗
PubMed1992

Selective release of spermine and spermidine from the rat striatum by N-methyl-D-aspartate receptor activation in vivo.

The intrastriatal infusion of N-methyl-D-aspartate (NMDA; 250-1,000 microM) via a dialysis cannula in anesthetized rats resulted in a marked and rapid increase in the concentrations of spermine and spermidine recovered in the dialysate. Extracellular concentrations of NMDA-released spermine and spermidine were calculated to be in the low micromolar range. Putrescine levels were not significantly affected by NMDA. The effects of NMDA (500 microM) were blocked by the previous systemic injection of MK-801 (3 mg/kg, i.p.) but were insensitive to the intrastriatal infusion of tetrodotoxin (1 microM). Intrastriatally infused kainate or quisqualate (1,000 microM) did not increase polyamine levels in the dialysate. Spermine and spermidine dialysate levels were also significantly increased by the infusion of high concentrations of K+ (greater than 100 mM), although the effects of K+ were considerably less marked than those of NMDA. Striatal polyamines are released into the extracellular space specifically by NMDA receptor activation. Because of their multiple effects on receptor- and voltage-operated cation channels, polyamines that are released by NMDA receptor activation may play an important role in phenomena already attributed to NMDA receptor stimulation, such as long-term potentiation, synaptic plasticity, and neurotoxicity.

Animals↗
PubMed1992

Pharmacological characterization of in vivo [3H]lfenprodil binding sites in the mouse brain.

Intravenous injection of 5 muCi of [3H]ifenprodil to mice resulted in an accumulation of radioactivity in the whole brain which was maximal at 5 min postinjection and then declined in a biphasic manner. When whole brain radioactivity was measured 2 h after [3H]ifenprodil injection, more than 65% of the incorporated label was displaced by i.p. administration (30 min before the radiotracer) of the ifenprodil chemical congener +/-alpha-(4-chlorophenyl)-4-(4- fluorophenylmethyl)-1-piperidine ethanol (SL 82.0715) (10 mg/kg). At this time, most of the radioactivity (80%) present in the brain comigrated with authentic [3H]ifenprodil. When administered 30 min before the radiotracer, several sigma ligands inhibited in vivo [3H]ifenprodil binding to the mouse brain with the following rank order of potency (ID50, mg/kg, i.p.): haloperidol (0.27) greater than ifenprodil (0.83) greater than SL 82.0715 (1.37) greater than BMY 14,802 (5.5) greater than 1,3-di-O-tolylguanidine (18). GBR 12909 (20 mg/kg, i.p.) and phencyclidine (30 mg/kg, i.p.) also inhibited this binding by 71 and 59%, respectively. In contrast, the N-methyl-D-aspartate receptor channel blockers 1-[1-(2-thienyl)cyclohexyl] piperidine and MK-801 (10 mg/kg, i.p.) failed to affect [3H]ifenprodil binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Comparative in vivo and in vitro regional selectivity of central omega (benzodiazepine) site ligands in inhibiting [3H]flumazenil binding in the rat central nervous system.

The in vivo selectivity for central omega (benzodiazepine) modulatory site subtypes of ligands from several chemical classes has been evaluated by measuring the displacement of the in vivo binding of [3H]flumazenil to several rat central nervous system structures differentially enriched in omega 1 and omega 2 sites. This labeling was prevented in a dose-related manner by the i.p. administration, 30 min before the radioligand, of several benzodiazepine derivatives, the cyclopyrrolone derivatives suriclone and zopiclone, the triazolopyridazine derivative CL 218,872 and the imidazopyridine derivative zolpidem. Most of the benzodiazepine derivatives studied displayed in vivo some selectivity for omega 2-enriched structures. In contrast, oxoquazepam and CL 218,872 were 2- to 3-fold more potent at preventing [3H]flumazenil binding in omega 1-enriched (cerebellum) than in omega 2-enriched structures. Maximal inhibitions by zolpidem of in vivo [3H]flumazenil binding [cerebellum (100%) > cerebral cortex (79%) > or = striatum (74%) > hippocampus (52%) > spinal cord (37%)] were related to the relative omega 1/omega 2 distribution ratio in each structure. These differences did not result from an uneven distribution of this compound in the central nervous system. Quantitative autoradiographic studies performed on 30 central nervous system regions showed a strong correlation between the in vitro and in vivo regional selectivity of zolpidem. For all the drugs studied there was a significant global correlation between their potency at inhibiting [3H]flumazenil binding in vitro and in vivo either in the cerebellum (P < .001) or in the spinal cord (P < .01) and between the in vitro and in vivo cerebellum/spinal cord selectivity. The differential in vivo selectivity of zolpidem may account for the reported hypnoselective profile of this imidazopyridine in the rodent.

Animals↗
PubMed1992

Dihydropyridine- and omega-conotoxin-resistant, neomycin-sensitive calcium channels mediate the depolarization-induced increase in internal calcium levels in cortical slices from immature rat brain.

In order to characterize pharmacologically voltage-operated calcium channels in the rat brain, we have developed a technique to measure intracellular calcium levels ([Ca++]i) in immature rat cortical slices loaded with the fluorescent calcium probe Fura-2. KCl depolarization caused a rapid and reversible increase in cortical [Ca++]i. A significant increase was already observed at 20 mM KCl and the maximal effect was obtained at 77 mM. This response was not modified when extracellular Na+ was substituted by the nonpermeant cation bis(2-hydroxyethyl)-dimethylammonium chloride and was insensitive to the Na+ channel blocker tetrodotoxin (1 microM). In the absence of extracellular Ca++, KCl (50 mM) failed to increase [Ca++]i. The KCl (50 mM)-induced increase in [Ca++]i was not affected by the L-type calcium channel blockers nifedipine and isradipine and was only partially inhibited (by less than 30% at 50 microM) by verapamil and diltiazem. In contrast, nimodipine prevented this response by 41% at 50 microM. Flunarizine (a nonselective T channel blocker) inhibited the KCl response by 47% at 30 microM, whereas nicergoline (another nonselective T channel blocker) reduced this entry by 74% at 300 microM (IC50 = 120 microM). Cyclandelate, an atypical calcium antagonist, inhibited KCl-induced increase in [Ca++]i with a maximal effect of 41% at 30 microM, whereas perhexiline was inactive. The KCl-induced rise in [Ca++]i was only marginally inhibited by omega-conotoxin with a maximal effect of 20% from 1 nM to 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycosides↗
PubMed1991

Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission.

Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response. Similarly, NAN-190 (0.1 microM) almost totally prevented the inhibition by 8-OH-DPAT (1 microM) of forskolin-stimulated adenylate cyclase activity in adult rat hippocampal slices but, per se, was without effect on the forskolin response. These results indicate that NAN-190 is a potent antagonist at postsynaptic 5-HT1A receptors in vitro. However, NAN-190 also potently antagonized (IC50 = 0.16 nM) the stimulation by norepinephrine of phosphoinositide turnover in rat cortical slices. In this respect NAN-190 was a 250-fold more potent antagonist than prazosin (IC50 = 49 nM). Thus, in addition to its 5-HT1A receptor antagonist properties, NAN-190 has potent alpha 1-adrenoceptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Difluoromethyl ornithine protects against the neurotoxic effects of intrastriatally administered N-methyl-D-aspartate in vivo.

The neurotoxic effects of intrastriatally administered N-methyl-D-aspartate (NMDA) (250 nmol), as measured by reductions in striatal choline acetyl transferase activity and by increased binding of the glial marker [3H]PK 11195 10 days later, were reduced by coinfusion of the irreversible ornithine decarboxylase inhibitor difluoromethylornithine (250 nmol) in the rat. The data suggest a crucial role for the polyamines in NMDA receptor-mediated neurotoxicity.

Animals↗
PubMed1991

The effects of N-methyl-D-aspartate and kainate lesions of the rat striatum on striatal ornithine decarboxylase activity and polyamine levels.

The intrastriatal injection of N-methyl-D-aspartate (NMDA) (250 nmol) produced a delayed and marked increase in striatal ornithine decarboxylase (ODC) activity and putrescine levels which peaked 6-15 h following the injection of NMDA. Striatal ODC activity subsequently returned to normal values while putrescine levels remained significantly elevated for up to 4 days following the lesion. NMDA produced an early and progressive decline in striatal spermine and spermidine levels, preceding the increase in ODC activity, with a maximum effect 2 h following injection. Spermidine levels returned to normal 6 h post-NMDA infusion, and subsequently increased to above normal levels 36 h and 4 days after the infusion of NMDA. This late increase in striatal spermidine levels paralleled an increase in the binding of the glial cell/macrophage marker [3H]PK 11195. Spermine levels tended to return to normal values 6 h after the injection of NMDA but may be further depressed at later intervals (15 h to 4 days). The intrastriatal injection of saline also resulted in a delayed increase in striatal ODC activity and putrescine levels, but these changes were minor compared to those produced by NMDA. Intrastriatal saline injection provoked no consistent change in striatal spermine or spermidine levels. The changes in polyamine metabolism produced by the intrastriatal injection of kainic acid (4 nmol) were only analysed at 6 and 15 h following injection but were qualitatively similar to those produced by NMDA although perhaps following a slightly more delayed time-course.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Regional pattern of increased omega 3 (peripheral type benzodiazepine) binding site densities in the rat brain induced by systemic injection of kainic acid.

The anatomical localization of the increase in omega 3 (peripheral type benzodiazepine) binding site densities (an index of glial reaction) following intraperitoneal injection of convulsant doses of kainic acid has been studied by autoradiography in the rat brain. Consistent increases in omega 3 site densities were observed in the olfactory, piriform and entorhinal cortices, amygdaloid nucleus, hippocampal formation and thalamus. In the hippocampal formation, the most pronounced increases were seen in the stratum lucidum of the CA3 field and in the stratum oriens and pyramidale of the CA1 and CA2 fields. This pattern of changes in omega 3 site densities closely paralleled the pattern of neuropathological alterations (assessed by histological methods) observed in these brain regions. Thus, omega 3 site autoradiography may provide a sensitive and reliable index of the neuronal damage resulting from kainic acid administration.

Affinity Labels↗
PubMed1991

Pharmacological characterisation and autoradiographic distribution of polyamine-sensitive [3H]ifenprodil binding sites in the rat brain.

Saturation studies with [3H]ifenprodil (in the presence of 3 microM (+)-3-PPP and 10 microM GBR 12909) demonstrated the presence of a high-affinity (Kd = 0.45 microM) population of binding sites in sagittal rat brain sections. This binding was inhibited by spermine (IC50 = 69 microM) and spermidine (IC50 = 623 microM) but not by putrescine (1 mM). Ifenprodil displaced this binding in a biphasic fashion with a high affinity component (IC50 = 0.992 microM) accounting for approximately 50% of the spermine-displaceable [3H]ifenprodil binding. The polyamine-sensitive [3H]ifenprodil binding sites were heterogenously distributed in the rat brain, the highest binding densities being found in the hippocampus and in the nucleus accumbens. The anatomical distribution of [3H]ifenprodil binding sites closely matches that previously reported for the N-methyl-D-aspartate (NMDA) receptor.

Animals↗