Search PubMed⌕ Search

Biomedical subjects

G Pepeu

Publications and source records attributed to G Pepeu.

At least 73 records · Page 4Linked to original sources
PubMed1996

Felbamate decreases synaptic transmission in the CA1 region of rat hippocampal slices.

The antiepileptic drug felbamate (FBM) is known to block N-methyl-D-aspartate receptor-mediated responses and to decrease voltage-sensitive Na+ and Ca+2 channels. The present work was aimed at investigating the actions of FBM on synaptic potentials in the hippocampus, a region frequently involved in epileptic discharges. In rat hippocampal slices, application of FBM (100-1300 microM, 10 min) elicited a concentration-dependent, fully reversible decrease in amplitude of electrically evoked population spikes recorded extracellularly from the CA1 pyramidal cell layer. In intracellular recordings, FBM (50-300 microM) decreased the amplitude of excitatory postsynaptic potentials and reduced the probability of firing action potentials upon synaptic activation. Action potential frequency adaptation (accommodation), which typically limits repetitive firing in CA1 pyramidal cells, was increased. By using a paired-pulse protocol, FBM (300 microM) depressed the amplitude of paired excitatory postsynaptic potentials, without affecting the facilitation of the second response. In nominally Mg(+2)-free solution, FBM (100 microM) blocked N-methyl-D-aspartate receptor-mediated synaptic excitatory postsynaptic potentials isolated by the presence of 10 microM 6-nitro-7-sulfamoylbenzo(f)quinoxaline hydrochloride, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, and 10 microM bicuculline or 25 microM picrotoxin. This effect was not reversed by the addition of 300 microM Gly. All these effects contribute to decrease excitatory synaptic transmission and are likely to limit neuron recruitment and propagation of epileptic discharges.

Animals↗
PubMed1995

Peripherally injected scopolamine differentially modulates acetylcholine release in vivo in the young and aged rats.

The effect of intraperitoneal administration of scopolamine (1 mg/kg) on acetylcholine (ACh) release in vivo in 3- and 24-month-old freely behaving rats was investigated in the cerebral cortex, hippocampus and striatum by means of transverse microdialysis. In the parietal cortex, the increase in ACh release after scopolamine administration was significantly greater in the old than in the young rats, reaching a maximum increase of about 600 and 300% in the old and young animals, respectively. In the hippocampus, scopolamine caused a larger increase in ACh release in the young (+900%) than in the old rats (+600%). In the striatum of aged rats, a 40% increase occurred only at 40 min after scopolamine administration while in the striatum of young animals the increase lasted for at least 2 h, reaching a maximum of about 100%. These findings demonstrate that the modulation of ACh release in vivo is affected in a different manner in the cerebral cortex than in the hippocampus and striatum by aging.

Acetylcholine↗
PubMed1995

Regulation of extracellular adenosine levels in the striatum of aging rats.

Extracellular adenosine concentrations, evaluated by microdialysis in the striatum of young and aged rats, were 66.8 +/- 0.7 and 71.6 +/- 1.0 nM, respectively. The adenosine deaminase inhibitor EHNA (100 microM) increased the extracellular adenosine levels in young rats only. The adenosine kinase inhibitor iodotubercidin (10 microM) brought about the same increase in young and aged rats. In aged rats the resting adenosine outflow was reduced by the N-methyl-D-aspartate (NMDA) receptor antagonist D-(-)-2-amino-7-phophonoheptanoic acid (D-AP7) (1 mM). It is concluded that extracellular levels of adenosine in the striatum are not affected by age, irrespective of the differences in adenosine deaminase activity and that the release of excitatory amino acids is responsible for much of resting adenosine outflow in aged but not in young rats.

2-Amino-5-phosphonovalerate↗
PubMed1995

Muscarinic receptor modulation of acetylcholine release from rat cerebral cortex and hippocampus.

An attempt to identify the muscarinic receptor subtypes involved in presynaptic modulation of acetylcholine (ACh) release from cortical and hippocampal slices was made by means of several muscarinic antagonists. Cortical and hippocampal slices prepared from adult rats were superfused with Krebs solution containing physostigmine; ACh content of the superfusate at rest and after electrical stimulation (1 Hz) was quantified by high performance liquid chromatography. The antagonists were added to the Krebs at the concentration of 1 microM. ACh release at rest was enhanced only in the cortex by (+/-)-5,11-dihydro-11-([(2-[2-[(dipropylamino)methyl]-1- piperidinyl)ethyl)amino]carbonyl)-6H-pyrido[2,3-b](1,4)- benzodiazepine-6-one (AFDX384), an M2/M4 selective antagonist. The evoked ACh release from the cerebral cortex was significantly increased by AFDX384, methoctramine, pirenzepine, M2/M4, M2 and M1 selective antagonists, respectively, and scopolamine. This finding suggests that M1, M2 and M4 presynaptic receptor subtypes could regulate evoked ACh release in the cortex. In hippocampal slices, the evoked ACh release was enhanced by AFDX384, pirenzepine and scopolamine but not by methoctramine. In this region ACh release seems therefore regulated only by M1 and M4 receptor subtypes. The M3 antagonist (+/-)-p-fluorohexahydro-sila-difenidol hydrochloride did not affect ACh release.

Acetylcholine↗
PubMed1995

The source of brain adenosine outflow during ischemia and electrical stimulation.

Adenosine outflow and adenosine and adenine nucleotide content of hippocampal slices were evaluated under two different experimental conditions: ischemia-like conditions and electrical stimulation (10 Hz). Five minutes of ischemia-like conditions brought about an 8-fold increase in adenosine outflow in the following 5 min during reperfusion, and a 2-fold increase in adenosine content, a 43% decrease in ATP, a 72% increase in AMP and a 30% decrease in energy charge (EC) at the end of the ischemic period. After 10 min of reperfusion ATP, AMP and EC returned to control values, while the adenosine content was further increased. Five minutes of electrical stimulation brought about an 8-fold increase in adenosine outflow that peaked 5 min after the end of stimulation, a 4-fold increase in adenosine content and an 18% decrease in tissue EC at the end of stimulation. After 10 min of rest conditions the adenosine content and EC returned to basal values. The origin of extracellular adenosine from S-adenosylhomocysteine (SAH) was examined under the two different experimental conditions. The SAH hydrolase inhibitor, adenosine-2,3-dialdehyde (10 microM), does not significantly modify the adenosine outflow evoked by electrical stimulation or ischemia-like conditions. This finding excludes a significant contribution by the transmethylation pathway to adenosine extracellular accumulation evoked by an electrical or ischemic stimulus, and confirms that the most likely source of adenosine is from AMP dephosphorylation.

Adenine Nucleotides↗
PubMed1995

Differential regulation by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors of acetylcholine release from the rat striatum in vivo.

The modulation of striatal cholinergic neurons by glutamatergic inputs was studied by monitoring the output of acetylcholine collected via a transversal microdialysis probe implanted into the striatum of freely moving rats. A transversal microdialysis membrane was inserted in the striatum and acetylcholine or GABA levels in the dialysate were measured. Acetylcholine levels in the dialysate were quantified by a high-performance liquid chromatography method with an electrochemical detector, while GABA levels were measured by a high-performance liquid chromatography method with a fluorescence detector. The dialysis membrane was perfused with Ringer solution containing 7 microM physostigmine sulphate and drugs, dissolved in the perfusion solution, were administered locally via the dialysis membrane. Local administration of the N-methyl-D-aspartate antagonist 3-[(RS)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (25-100 microM) brought about a decrease in striatal acetylcholine output which was dose-dependent, reversible and partially antagonized by 100 microM N-methyl-D-aspartate. On the other hand, local administration of the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline was followed by an increase in acetylcholine output which reached a maximum of about +55% at 12.8 microM 2,3-dihydroxy-6-nitro-7-sulfamoil-benzo(F)quinoxaline and was readily reversed when the drug was withdrawn from the perfusion solution. Local administration of the non-N-methyl-D-aspartate receptor agonist (S)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (50 and 200 microM) decreased acetylcholine output and this effect was reversed by simultaneous perfusion with the GABA antagonist bicuculline (50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Differential effects of amyloid peptides beta-(1-40) and beta-(25-35) injections into the rat nucleus basalis.

The nucleus basalis of male Charles River Wistar rats was injected with 10 micrograms of the beta-amyloid peptides beta-(1-40) and beta-(25-35) and changes in the morphology of the lesioned area, the release of acetylcholine from the cortex, and in behavior were investigated. Injections of saline and a scrambled (25-35) peptide were used as controls. One week after lesioning, a Congo Red-positive deposit of aggregated material was found at the beta-peptides injection site, which lasted for about 21 days in the case of the beta-(25-35) peptide and at least two months for beta-(1-40). No deposit was detected after scrambled peptide injection. At one week post injection, an extensive glial reaction surrounded the injection site of all peptides and saline as well. Such a reaction was still present but rather attenuated after two months. A decrease in the number of cholinergic neurons was detected in the nucleus basalis after one week with all treatments except saline. After two months, a reduction in the number of choline acetyltransferase-immunopositive neurons was still detectable in the rats injected with beta-(1-40) but not in the beta-(25-35)-or scrambled-injected. The reduction in choline acetyltransferase immunoreactivity was closely paralleled by a decrease in basal acetylcholine release from the parietal cortex ipsilateral to the lesion. Disruption of object recognition was observed in the first weeks after beta-(25-35) peptide injection, whereas the beta-(1-40) peptide impaired the performance only two months after lesion. Rats with lesions induced by beta-peptides may be a useful animal model of amyloid deposition for investigation of the pathogenetic mechanisms leading to Alzheimer's disease.

Acetylcholine↗
PubMed1994

Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition.

Male Wistar rats (3- and 20-month-old) were perfused i.c.v. with 1.5 micrograms of either nerve growth factor (NGF) or cytochrome C daily for 14 days. At the end of the infusion, the object-recognition test was carried out and extracellular acetylcholine levels (ACh) were measured in the cortex and hippocampus by transversal microdialysis technique. In 20-month-old control rats, the cortical and hippocampal ACh levels were 35 and 45% lower, respectively, than in 3-month-old rats and the ability to discriminate between a familiar and new object was impared. In the old rats treated with NGF, the ACh release as well as the behavioral performance showed no difference from those of young rats. These findings indicate that both ACh levels and memory impairment are improved in aged rats by NGF treatment and suggest that there is a relationship between object recognition and the activity of the forebrain cholinergic system.

Acetylcholine↗
PubMed1994

In vivo regulation of extracellular adenosine levels in the cerebral cortex by NMDA and muscarinic receptors.

The adenosine concentration in samples of perfusate was determined 24 h after implantation of microdialysis fibre in the cortex. High performance liquid chromatography coupled with a fluorometric detector was used. K+ (100 mM) depolarization was followed by a 2- to 4-fold increase in adenosine efflux. The addition of tetrodotoxin (1 microM) to the perfusate was followed by a decrease in spontaneous and K(+)-evoked adenosine efflux. The increase induced by high K+ was markedly inhibited by the NMDA receptor antagonist, D(-)-2-amino-7-phosphonoheptanoic acid (1 mM, D-AP7), but not by the muscarinic receptor antagonist, atropine (1.5 microM). The acetylcholine esterase inhibitor, physostigmine (7 microM), and the muscarinic receptor agonist, oxotremorine (100 microM), significantly enhanced the K(+)-evoked increase in adenosine. The spontaneous efflux of adenosine was not modified by any of the drugs tested. A neurotoxic lesion of the cholinergic pathway innervating the cortex, although inducing a marked decrease in cortical choline acetyltransferase activity, did not significantly modify the cortical adenosine efflux. It is concluded that, under K(+)-depolarizing conditions, adenosine efflux is triggered by excitatory amino acids and enhanced by muscarinic activation.

2-Amino-5-phosphonovalerate↗
PubMed1994

Administration of amyloid beta-peptides into the medial septum of rats decreases acetylcholine release from hippocampus in vivo.

The septum of male Wistar rats was injected with synthetic beta-amyloid fragments, beta 12-28, beta 25-35 and beta 1-40, and hippocampal acetylcholine (ACh) release was evaluated by transversal microdialysis. A marked decrease in basal and K(+)-evoked ACh release was found 7 or 21 days after injection of 5 nmol of beta 12-28 and beta 25-35, or 3 nmol of beta 1-40, respectively. These data indicate that septal injection of beta-amyloid peptides causes hypofunction of the septo-hippocampal cholinergic system.

Acetylcholine↗
PubMed1994

Dysfunction of the brain cholinergic system during aging and after lesions of the nucleus basalis of Meynert.

In order to establish how closely the models mimic aging and Alzheimer's disease, a comparison was made, using the extensive literature available, between brain cholinergic dysfunction in aging animals and man, and between that in animals with lesions of the nucleus basalis of Meynert and in subjects affected by Alzheimer's disease. It is concluded that cholinergic dysfunction in the aging rat closely resembles that in aging man. A similarity can also be found between the cortical dysfunction induced by lesions of the nucleus basalis and that occurring in patients with Alzheimer's disease. However, cholinergic dysfunction only represents a limited aspect of the neorotransmitter deficits and neuropathological alterations of the disease.

Acetylcholine↗
PubMed1994

Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats.

A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 micrograms twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained. Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.

Animals↗
PubMed1994

Memory disorders: novel treatments, clinical perspective.

The aging of the society is accompanied by a strong pressure to develop drugs to treat age-related memory disorders. This paper examines the discrepancy between the results of preclinical tests, which have identified a large number of putative cognition enhancers, and the limited clinical efficacy of most of them. The predictivity of the preclinical tests is discussed, and the criteria for evaluating the therapeutic efficacy of the cognition enhancers are examined. An analysis is made of the novel treatments presently available or under investigation. In light of the results of the trials with tacrine a warning is given not to expect striking clinical improvements by only attempting to restore signal transmission, disrupted by aging and dementia, without modifying the underlying morphological alterations.

Alzheimer Disease↗
PubMed1994

Glutamatergic regulation of acetylcholine output in different brain regions: a microdialysis study in the rat.

The glutamatergic regulation of cortical and striatal cholinergic neurons was investigated by measuring ACh output from the parietal cortex and striata of freely moving rats after administration of the competitive NMDA-receptor antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). It has been shown that intracerebroventricular administration of 5 nmol of CPP brings about a long lasting 100% increase in ACh output from the parietal cortex but does not affect ACh output from the striatum. Conversely, local perfusion of the striata with 50 microM CPP results in a 45% decrease in ACh output from the striatum but has no effect on parietal ACh output. The decrease in striatal ACh output induced by CPP is antagonized by concurrent perfusion with NMDA. In conclusion, glutamate may exert both inhibitory and excitatory modulatory effects on ACh output, through NMDA receptors, according to the neuronal circuitry existing in different brain regions.

Acetylcholine↗
PubMed1994

NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study.

The modulation of the septohippocampal cholinergic pathway by glutamatergic or GABAergic inputs was studied by monitoring the outflow of ACh collected via a transversal microdialysis probe implanted into the hippocampus and other brain areas of freely moving rats. In one set of experiments a transversal microdialysis membrane was inserted in the dorsal hippocampus, drugs were administered intracerebroventricularly through a cannula implanted in the lateral ventricle, and ACh outflow in the dialysate was measured by an HPLC method with an electrochemical detector. The dialysis membrane was usually perfused with Ringer's solution containing 7 microM physostigmine sulfate. Intracerebroventricular injections of the NMDA antagonists 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 1-50 nmol), MK801 (0.5-20 nmol), and D(-)-2-amino-7-phosphonoheptanoic acid (100 nmol) brought about an increase in hippocampal ACh outflow while the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione (0.25-20 nmol) was without effect. The increase in ACh outflow following CPP administration was dose dependent and reached a maximum of about 500%. It was abolished by TTX (0.5 microM) delivered locally to the hippocampus via the dialysis membrane and prevented by intracerebroventricular injection of the GABA agonist muscimol (5 nmol). In a second set of experiments, one microdialysis membrane was inserted in the dorsal hippocampus to detect ACh outflow and another in the septum to administer drugs locally and at the same time detect septal GABA outflow. The septal dialysis membrane was perfused with Ringer's solution without physostigmine, and GABA levels in the dialysate were measured by an HPLC method with a fluorescence detector. CPP (100 microM) perfused through the septum resulted in a decrease in septal GABA outflow and a concomitant increase in hippocampal ACh outflow. Muscimol (100 microM) administration into the septum abolished the effect of CPP on hippocampal ACh outflow but did not affect septal GABA outflow. These results demonstrate that in the septum NMDA receptors tonically activate GABAergic neurons which in turn inhibit the cholinergic septohippocampal neurons.

2-Amino-5-phosphonovalerate↗