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Biomedical subjects

Giancarlo Pepeu

Publications and source records attributed to Giancarlo Pepeu.

12 recordsLinked to original sources
PubMed2006

Neuronal control of the cardiac responses to osmotic stress in the gastropod limpet Patella caerulea.

Mediterranean limpets Patella caerulea were exposed to different salinity conditions and treated with drugs interfering with neuronal control of heartbeat. Heart rate was monitored using a non-invasive method. Limpets were superfused with control (33 g l(-1)), hyposaline (0 and 10 g l(-1)) or hypersaline (56 and 66 g l(-1)) artificial seawater. Under osmotic stress the limpets showed an initial increase of heart rate, followed by acardia, particularly under hyposalinity. The tachycardia observed after exposure to 56 g l(-1) was abolished in the animals injected with a selective sodium channel blocker, tetrodotoxin (TTX), or with a serotoninergic antagonist, methysergide. Injection of TTX also partly prevented the acardia occurring at 0 g l(-1). The acardia was completely prevented after injection with atropine and benzoquinonium, two selective cholinergic antagonists. These findings indicate that cardiac responses of P. caerulea to variations in external salinity are regulated by an extrinsic neuronal control involving the serotoninergic and the cholinergic systems in the tachycardic and acardic responses, respectively.

Adaptation, Physiological↗
PubMed2006

Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice.

In 7-month-old TgCRND8 mice, the extracellular cortical acetylcholine levels in vivo, the number and morphology of cholinergic neurons in the nucleus basalis magnocellularis and the ability to acquire an inhibitory avoidance response in the step-down test were studied. The TgCRND8 mouse brain is characterized by many beta-amyloid plaques, reduced neuronal and axonal staining, white matter demyelination, glia reaction and inducible nitric oxide synthase immunoreactivity. Choline acetyltransferase immunoreactivity in the nucleus basalis magnocellularis was significantly decreased. Basal and potassium-stimulated extracellular acetylcholine levels, investigated by microdialysis, and m2 muscarinic receptor immunoreactivity were reduced in the cortex of TgCRND8 mice, and scopolamine administration increased cortical extracellular acetylcholine levels in control but not in TgCRND8 mice. A cognitive impairment was demonstrated in the step-down test. These findings demonstrate that neuronal damage and cholinergic dysfunction in vivo underlie the impairment in learning and memory functions in this mouse model of Alzheimer's disease.

Acetylcholine↗
PubMed2005

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent.

Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower beta-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.

Acetylcholine↗
PubMed2005

Tetrodotoxin prevents copper-induced bradycardia in gastropod limpets.

Acute exposure to waterborne copper is followed by a reduction in heart rate in gastropod limpets. In order to understand the mechanism of this effect, exposure to copper (0.25 or 0.5 mg l(-1); for 3 and 6 h) was combined with an injection of tetrodotoxin (TTX, 20 microl, 0.5 or 1 microM), a natural toxin that inhibits the propagation and transmission of impulses in excitable tissues. Experiments were performed on the Mediterranean limpet Patella caerulea, using a non-invasive method for the recording of cardiac activity. TTX did not affect the bradycardic effect of the cholinergic agonist carbachol. However, this toxin significantly antagonized the bradycardia induced by 0.25 and 0.5mg l(-1) of copper exposure and prevented the acardia observed in some limpets exposed to 0.5mg l(-1) of copper for 6h. These results are consistent with the hypothesis that the inhibitory action of copper on limpet cardiac activity involves an extrinsic, cholinergic neuronal control.

Animals↗
PubMed2004

S 18986, a positive modulator of AMPA receptors with cognition-enhancing properties, increases ACh release in the hippocampus of young and aged rat.

The effect of S 18986, positive AMPA receptor modulator, on acetylcholine (ACh), gamma-aminobutyric acid (GABA) and glutamate (Glu) release from the hippocampus of freely moving young and aged rats was investigated by microdialysis coupled to HPLC. The cognition-enhancing properties were evaluated by a passive avoidance test. In 3 month-old rats, S 18986 (10 mg/kg i.p.) increased by 70% ACh release, which returned to basal level within 2 h, while 3 mg/kg had no effect. In 22 month-old rats, both 3 and 10 mg/kg i.p. induced a long lasting increase in ACh release, as large as that induced by 10 mg/kg in young rats. S 18986 did not modify GABA and glutamate release. No effect on general behavior was observed, but S 18986 at both doses prevented the disrupting effect of scopolamine (1 mg/kg i.p.) on passive avoidance acquisition.

Acetylcholine↗
PubMed2004

A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone.

The aim of the study was to investigate whether the antidepressant trazodone (TRZ), a serotonin-2 receptor antagonist/reuptake inhibitor, modifies gamma-amino-butyric acid (GABA) extracellular levels in the cerebral cortex, by acting on 5-HT(2A) receptors, and through this mechanism increases 5-HT levels. For this purpose the effect of TRZ on the release of GABA was studied in adult male rats in synaptosomes, cortical slices, and "in vivo" by microdialysis. In cortical slices, the release of both GABA and 5-HT was determined. GABA and 5-HT were identified and their levels quantified by HPLC. The inhibition of 5-HT uptake by TRZ was also measured. In synaptosomes, TRZ antagonized dose-dependently, at concentrations from 10(-10) to 10(-6) M, the increase in GABA release induced by (+/-)DOI, a 5-HT(2A/2C) agonist, and the alpha receptor agonist phenylephrine, both 10(-6) M. The pIC50 values were 8.31+/-0.24, and 5.99+/-0.52, respectively. In the same preparation, [3H]5-HT accumulation was inhibited by citalopram and TRZ with pIC(50) of 7.8+/-0.44 and 5.9+/-0.09, respectively, a finding confirming the weak activity of TRZ in comparison with a SSRI. In cortical slices, TRZ exerted a biphasic effect on GABA release. At concentrations from 10(-10) to 10(-7) M it inhibited and from 10(-6) to 10(-4) M increased GABA release. 5-HT release was enhanced by TRZ throughout the entire range of concentrations tested. However, the increase was delayed after low and rapid after high concentrations. AMI-193, a 5-HT(2A) antagonist (10(-10) to 10(-5) M), reduced GABA release in a dose-response manner, while it induced an increase of 5-HT outflow. On the contrary, (+/-)DOI (10(-10) to 10(-5) M) increased GABA release and inhibited 5-HT levels. Perfusion with the GABA(A) receptor antagonist bicuculline was also followed by an increase in 5-HT release. In microdialysis experiments, TRZ 1.25 mg kg(-1) s.c. brought about a decrease in GABA extracellular levels, while an increase was found after the dose of 2.5 mg kg(-1). These findings demonstrate that TRZ, at concentrations which do not inhibit 5-HT uptake, reduces the cortical GABAergic tone by decreasing GABA extracellular levels, through the blockade of 5-HT(2A) receptors. The attenuation of GABAergic tone is responsible for an increase in 5-HT levels. A further increase also results from 5-HT uptake inhibition caused by higher doses of TRZ. The ensuing high 5-HT levels enhance GABA release, which in turn inhibits 5-HT release.

Algorithms↗
PubMed2002

Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway.

Injection into the nucleus basalis of the rat of preaggregated Abeta(1-42) produced a congophylic deposit and microglial and astrocyte activation and infiltration and caused a strong inflammatory reaction characterized by IL-1beta production, increased inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS) expression. Many phospho-p38MAPK-positive cells were observed around the deposit at 7 days after Abeta injection. Phospho-p38MAPK colocalized with activated microglial cells, but not astrocytes. The inflammatory reaction was accompanied by cholinergic hypofunction. We investigated the protective effect of the selective COX-2 inhibitor rofecoxib in attenuating the inflammatory response and neurodegeneration evoked by Abeta(1-42). Rofecoxib (3 mg/kg/day, 7 days) reduced microglia and astrocyte activation, iNOS induction, and p38MAPK activation to control levels. Cholinergic hypofunction was also significantly attenuated by treatment with rofecoxib. We show here for the first time in vivo the pivotal role played by the p38MAPK microglial signal transduction pathway in the inflammatory response to the Abeta(1-42) deposit.

Acetylcholine↗
PubMed2002

An autocrine role for pituitary GABA: activation of GABA-B receptors and regulation of growth hormone levels.

There is increasing evidence suggesting that the neurotransmitter gamma-aminobutyric acid (GABA) is a local factor involved in the regulation of endocrine organs. Examples of such functions are documented in the pancreas, but recent results suggest that GABA may act in a similar way in the pituitary, in which GABA receptors are expressed and pituitary growth hormone (GH) cells provide a source of GABA. We hypothesised that GABA secreted in somatotropes may act as an autoregulatory signaling molecule. To test this hypothesis we first examined the nature of GABA receptors expressed by GH cells. RT-PCR analysis demonstrated that GABA-B receptor subunits R1 and R2 are present in the whole rat pituitary. Laser microdissection of immunostained GH cells, followed by RT-PCR as well as immunoelectron microscopy, showed that GABA-B receptors are expressed on somatotropes. To investigate GABA-B receptor function in somatotropes, we used rat GH3 adenoma cells, which, like pituitary GH cells, express GABA-B R1 and R2 (as assessed by RT-PCR and immunoelectron microscopy) and produce GABA (checked by high performance liquid chromatography). After inhibition of endogenous GABA synthesis, GH production was stimulated by baclofen, a chromatography). After inhibition of endogenous GABA synthesis, GH production was stimulated by baclofen, a GABA-B receptor agonist. By contrast, blocking GABA-B receptors by an antagonist, phaclofen, decreased GH levels. We conclude that in GH-producing cells, GABA acts as an autocrine factor via GABA-B receptors to control GH levels.

Animals↗
PubMed2002

Bidirectional modulation of spatial working memory by ethanol.

BACKGROUND: It is common knowledge that ethanol causes cognitive and memory impairments. Although these deficits are attributed to its central depressant properties, ethanol has biphasic effects and at low doses can produce excitatory actions. METHODS: Here we examined whether ethanol could have biphasic effects on performance in a delayed alternation task in a T-maze, a behavioral test of working memory. RESULTS: A dose-response study showed that intermediate doses of ethanol (1 g/kg) were associated with impairments of working memory in rats, as assessed at short intertrial intervals (10 sec). In contrast, at longer delays (120 sec), when the delayed alternation performance was reduced markedly in controls, a lower dose of ethanol (0.5 g/kg) significantly improved working memory. CONCLUSIONS: These results demonstrate a dose-dependent, bidirectional effect of ethanol on working memory and implicate the prefrontal cortex, the site of working memory function, as a target of ethanol action. The cognitive improvements caused by low, excitatory doses of ethanol may be perceived as rewarding and could have relevance for chronic ethanol consumption in humans.

Animals↗
PubMedDate not supplied

Neutrophils CD11b and fibroblasts PGE(2) are elevated in Alzheimer's disease.

To evaluate whether inflammation-like mechanisms present in the brain of Alzheimer's disease (AD) patients are reflected in the periphery, the expression of CD11b in peripheral blood neutrophils and the expression and activity of inflammatory markers in cultured skin fibroblasts were examined. We found significantly higher levels of CD11b in neutrophils from sporadic AD patients than in controls and this elevation was positively correlated with disease severity and progression rate of mental decline. Cultured skin fibroblasts from familial (FAD) and sporadic AD patients and from controls were immunopositive for both isoforms of cyclooxygenase with no differences between groups. In unstimulated culture, the production of prostaglandin-E2 in the medium was significantly higher in fibroblasts from sporadic AD and FAD patients than in controls, and this elevation was reverted by the addition of 25 microM of ibuprofen. Our findings provide further evidence of the presence of inflammatory and immuno-related markers in the periphery of AD patients and support those studies indicating the beneficial effects of anti-inflammatory therapy in AD.

Aged↗
PubMedDate not supplied

Changes in acetylcholine extracellular levels during cognitive processes.

Measuring the changes in neurotransmitter extracellular levels in discrete brain areas is considered a tool for identifying the neuronal systems involved in specific behavioral responses or cognitive processes. Acetylcholine (ACh) is the first neurotransmitter whose diffusion from the central nervous system was investigated and whose extracellular levels variations were correlated to changes in neuronal activity. This was done initially by means of the cup technique and then by the microdialysis technique. The latter, notwithstanding some technical limitations, makes it possible to detect variations in extracellular levels of ACh in unrestrained, behaving animals. This review summarizes and discusses the results obtained investigating the changes in ACh release during performance of operant tasks, exposition to novel stimuli, locomotor activity, and the performance of spatial memory tasks, working memory, and place preference memory tasks. Activation of the forebrain cholinergic system has been demonstrated in many tasks and conditions in which the environment requires the animal to analyze novel stimuli that may represent a threat or offer a reward. The sustained cholinergic activation, demonstrated by high levels of extracellular ACh observed during the behavioral paradigms, indicates that many behaviors occur within or require the facilitation provided by the cholinergic system to the operation of pertinent neuronal pathways.

Acetylcholine↗