Nanostructure and nanomechanics of cement: polydisperse colloidal packing.

Cement setting and cohesion are governed by the precipitation and growth of calcium-silicate-hydrate, through a complex evolution of microstructure. A colloidal model to describe nucleation, packing, and rigidity of calcium-silicate-hydrate aggregates is proposed. Polydispersity and particle size dependent cohesion strength combine to produce a spectrum of packing fractions and of corresponding elastic properties that can be tested against nanoindentation experiments. Implications regarding plastic deformations and reconciling current structural characterizations are discussed.

Influence of different anaesthetics on extracellular aminoacids in rat brain.

We used different anaesthetic procedures to study the possible effects of anaesthesia on extracellular aminoacid concentration in rat brain. Glutamate, aspartate and glycine concentrations were determined by HPLC in samples collected from the right fronto-parietal region of the rat brain cortex by transcerebral microdialysis before and up to 2 h following anaesthesia induction. Anaesthesia induced by ketamine, alone or in association with xylazine, caused a significant decrease in the levels of glutamate, aspartate and glycine, compared to before anaesthesia values (range: 27-72% according to the time of sampling and to the anaesthetic used). Inhalation anaesthesia with halothane (3%) in N2O/O2 mixture produced no significant effects on aminoacid levels. Equitensine (pentobarbital in association with chloral hydrate and ethanol) and pentobarbital also had no significant effect on glutamate, aspartate and glycine levels during anaesthesia. This demonstrates that some anaesthetics alter excitatory aminoacid release and suggests that Equitensine may represent an easy and reliable method to induce a long lasting anaesthesia associated without changes in excitatory aminoacid extracellular concentration.

Inhibition of prostanoid synthesis protects against neuronal damage induced by focal ischemia in rat brain.

Changes in prostanoids concentration and effects of the non-specific COX inhibitor indomethacin on prostanoids levels and extension of tissue damage were studied following focal ischemia induction in the fronto-parietal region of rat brain. Ischemia was induced in animals bearing a transcerebral microdialysis probe by injection of Rose Bengal, a photosensitive dye, followed by light activation. Prostanoid levels were determined in the dialysate using immunoenzymatic techniques. PGD2 levels rose significantly up to 237+/-22 pg/ml compared to a basal level measured before ischemia induction which was below the detection limit. TXB2 changes were smaller and had a different time course. Treatment with indomethacin abolished the ischemia-induced PGD2 release and reduced the extent of injury to the area by 43+/-3.7%. These results suggest that prostanoid release may play an important role in neurodegenerative processes and that cyclooxygenase inhibitors may contribute to protect against cerebral tissue damage.

The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat.

Focal ischemia was induced in the fronto-parietal region of rat brain, by injection of Rose Bengal, followed by light activation. Focal ischemia was accompanied by formation of PGD(2) peaking 60-90 min post irradiation and declining thereafter. Increased Cycloxygenase-2 (COX-2) expression was also observed. Control ischemic rats showed distinct morphological alterations with necrosis of neurons, glial cells and blood vessels, surrounded by a halo with pyknotic cells with cytoplasm swelling and vacuolization. Compound SC58236, a selective COX-2 inhibitor, dose-dependently prevented, ischemia-induced eicosanoid formation (area under the curve (AUC) of controls: 3.11 +/- 0.87; AUC of 20 mg/kg SC58236: 0.39 +/- 0.24), and caused significant reduction of damaged area (30.7 and 18.9% at SC58236 20 and 6.6 mg/kg), suggesting that selective inhibitors of COX-2 are neuroprotective.

The interaction of antidepressant drugs with enteric 5-HT7 receptors.

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.

Influence of fluoxetine and litoxetine on 5-HT4 receptor-mediated relaxation in the rat isolated oesophagus.

The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant antagonism of litoxetine response (P = 0.037: ANOVA for continuous-by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 microM) increased the relaxant effects of 5-HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5-HT, without changing its potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4 receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that blockade of 5-HT reuptake can participate in the action of litoxetine, since fluoxetine, a 5-HT reuptake inhibitor equipotent to litoxetine, was ineffective in the same range of concentrations. The antimuscarinic activity of litoxetine, previously demonstrated in the isolated guinea-pig intestine, played a role at concentrations greater than 1 microM. The 5-HT-releasing action of litoxetine could account for the potentation by litoxetine of 5-HT-induced relaxation in tissues from untreated rats, which was reversed by pCPA treatment. Under these conditions, litoxetine depressed relaxations to high 5-HT concentrations only. In tissues from untreated rats, fluoxetine slightly but unsurmountably antagonized 5-HT-induced relaxations, thus confirming previous observations in the guinea-pig small intestine.

Effect of acute alcohol on ischemia-induced glutamate release and brain damage.

Epidemiological studies show that chronic ethanol consumption at high doses enhances the risk of cerebral stroke. The mechanisms responsible for the greater vulnerability of alcoholics' brains to stroke have to be completely understood, but a role for excitatory amino acids has been suggested. In order to study the interaction between alcohol and ischemia, we investigated the effect of acute alcohol administration in a model of focal cerebral ischemia. In particular, we evaluated the release of glutamate and aspartate from the cerebral frontal cortex by a transdialysis technique. Alcohol was acutely administered at 1.5 and 3.0 g/kg ip. During the period of maximal alcoholemia, ethanol almost abolished the ischemia-induced release of glutamate leading to glutamate values around or below the basal. Aspartate levels were unaltered both following ischemia and alcohol+ischemia. The decrease in glutamate release, however, was not accompanied by a significant reduction of the extension of the damaged area assessed by histological analysis.

2-Phenylmelatonin: a partial agonist at enteric melatonin receptors.

The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 microM) caused a concentration-dependent contractile response. The potency value (-log EC50) was 9.3 +/- 1.0. The maximum effect was 25 +/- 4%, of that elicited by the maximally effective concentration (0.3 microM) of 5-HT and 43 +/- 3%, of that by the maximally effective concentration (10 microM) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 microM), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 microM prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist.

Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly.

Depression is the most prevalent functional psychiatric disorder in late life. The problem of motor disorders associated with antidepressant use is relevant in the elderly. Elderly people are physically more frail and more likely to be suffering from physical illness, and any drug given may exacerbate pre-existing diseases, or interact with other drug treatments being administered for physical conditions. Antidepressants have been reported to induce extrapyramidal symptoms, including parkinsonism. These observations prompted us to review the neurobiological mechanism that may be involved in this complex interplay including neurotransmitters and neuronal circuits involved in movement and emotion control and their changes related to aging and disease. The study of the correlations between motor and mood disorders and their putative biochemical bases, as presented in this review, provide a rationale either to understand or to foresee motor side effects for psychotropic drugs, in particular antidepressants.