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Biomedical subjects

M Geoffroy

Publications and source records attributed to M Geoffroy.

At least 19 recordsLinked to original sources

Formation of a phosphorus-phosphorus bond by successive one-electron reductions of a two-phosphinines-containing macrocycle: crystal structures, EPR, and DFT investigations.

Chemical and electrochemical reductions of the macrocycle 1 lead to the formation of a radical monoanion anion [1](*)(-) whose structure has been studied by EPR in liquid and frozen solutions. In accord with experimental (31)P hyperfine tensors, DFT calculations indicate that, in this species, the unpaired electron is mainly localized in a bonding sigma P-P orbital. Clearly, a one-electron bond (2.763 A) was formed between two phosphorus atoms which, in the neutral molecule, were 3.256 A apart (crystal structure). A subsequent reduction of this radical anion gives rise to the dianion [1](2)(-) which could be crystallized by using, in the presence of cryptand, Na naphthalenide as a reductant agent. As shown by the crystal structure, in [1](2)(-), the two phosphinine moieties adopt a phosphacyclohexadienyl structure and are linked by a P-P bond whose length (2.305(2) A) is only slightly longer than a usual P-P bond. When the phosphinine moieties are not incorporated in a macrocycle, no formation of any one-electron P-P bond is observed: thus, one-electron reduction of 3 with Na naphthalenide leads to the EPR spectrum of the ion pair [3](*)(-) Na(+); however, at high concentration, these ion pairs dimerize, and, as shown by the crystal structure of [(3)(2)](2)(-)[(Na(THF)(2))(2)](2+) a P-P bond is formed (2.286(2) A) between two phosphinine rings which adopt a boat-type conformation, the whole edifice being stabilized by two carbon-sodium-phosphorus bridges.

Journal Article↗

Role of hydroxyl radicals and singlet oxygen in the formation of primary radicals in unsaturated lipids: a solid state electron paramagnetic resonance study.

Primary radicals were generated by UV photolysis of samples of trilinolein, at 77 K and under a controlled atmosphere. The resulting EPR spectra clearly show that the amount of radicals is dependent on the purity of the lipid, the exposure to visible light in the presence of a photosensitizer and oxygen, and, finally, the presence of an antioxidant. These solid state EPR experiments indicate that if all of the elements for the production of singlet oxygen (Rose Bengal, molecular oxygen, and visible light) are not present, primary radicals are practically not generated. They also point out the various steps of the oxidation mechanism: formation of singlet oxygen, which reacts with the lipid to form a hydroperoxide; and photolytic formation of the hydroxyl radical, which reacts with the frozen lipid to generate primary lipidic radicals. This constitutes a new method for investigating lipid oxidation and studying the influence of photosensitizers and molecules that are likely to react with singlet oxygen.

Electron Spin Resonance Spectroscopy↗

Gold(I) and Gold(0) Complexes of Phosphinine-Based Macrocycles.

A "CO-like matrix", showing coordination analogous to that of carbonyl groups, is provided by silacalix[4]phosphinine macrocycles. Reaction with Au(I) leads to the first gold(I) complexes of macrocycles, which can be reduced with sodium or potassium to the paramagnetic gold(0) complexes (an example is shown), as evidenced by cyclic voltammetry and EPR spectroscopy.

Journal Article↗

Synthesis and conformational analysis of a novel type of spin labelled bicyclonucleoside based on a tetrahydrofurano[2,3-c]pyrrolidine sugar skeleton.

Bicyclonucleosides bearing a 5-deoxy-5-N-hydroxyamino-3,N5-(1,1-ethano)-beta-D-furanosyl sugar moiety (15-18) have been prepared by glycosidation of the corresponding bicyclosugars obtained via an intramolecular reverse Cope elimination. The configuration of the asymmetric carbon of the 1,1-ethano bridge is the most important factor directing the conformation of the N-hydroxypyrrolidine ring and its invertomers ratio as shown by variable temperature H NMR experiments.

Carbohydrates↗

Radical intermediates and antioxidants: an ESR study of radicals formed on carnosic acid in the presence of oxidized lipids.

Carnosic acid, an antioxidant extracted from rosemary, is shown to produce radicals when in contact with oxidized methyl oleate in the absence of air above 50 degrees C. Two radical species are formed: the first one, stable up to approximately 110 degrees C, is an hydroxy-phenoxy radical whose ESR spectrum was analyzed by studying its temperature dependence and its sensitivity to deuterium/proton exchange. The second species was observed above 110 degrees C, its ESR spectrum was identical to the spectrum obtained when carnosol, another antioxidant extracted from rosemary, was heated at the same temperature in the presence of oxidized lipid. This observation is probably due to the transformation of carnosic acid into carnosol; the analysis of the corresponding ESR spectrum suggests the formation of a keto phenoxy radical exhibiting a great delocalization of the unpaired electron.

Abietanes↗

Spin-labelled sulfur containing neoglycolipids.

A neoglycolipid of structure beta-D-Glcp-S-(CH2)3N(OH)(CH2)4-O-cholest-5-en-3 beta-yl has been prepared in fair overall yield by reduction of the nitrone obtained by condensation of beta-D-Glcp-S-(CH2)3NHOH and OCH-(CH2)3-O-cholest-5-en-3 beta-yl. This synthetic procedure is very flexible, allowing a large range of lengths for the spacer arm, different positions for the NOH group along the spacer arm chain and the replacement of the sulfur by other bio-isosteric groups. The new neoglycolipid spontaneously oxidized to the corresponding nitroxide free radical whose EPR spectrum gave information on its conformational equilibrium which was further studied by molecular mechanics.

Glycolipids↗

The effect of imipramine and lithium on "learned helplessness" and acetylcholinesterase in rat brain.

The effect of short- and long-term treatment with imipramine and lithium on shock stress-induced escape failures in a shuttlebox (the "learned helplessness" model of depression) was investigated in rats. Acetylcholinesterase (AChE) activity was measured in the frontal cortex, hippocampus and striatum after the shuttlebox test. Imipramine was found to normalize escape behavior, whereas lithium further aggravated escape behavior. No correlation was found between escape behavior and AChE activity in the three brain areas investigated. However, a significant decrease in AChE activity in striatum was found in rats exposed either to shock stress and no drug treatment or to drug treatment and no shock stress. In rats exposed to the combination of shock stress and drug (imipramine or lithium), a slight or no decrease of AChE activity occurred. Exposure to shock stress alone produced no changes in AChE activity in the hippocampus and frontal cortex. In conclusion, lithium did not have an antidepressant effect on "learned helplessness" and AChE activity was not correlated to escape behavior. However, both imipramine and lithium normalized the decreased level of AChE activity in striatum in rats exposed to shock stress.

Acetylcholinesterase↗

Reduction of desensitization of a glutamate ionotropic receptor by antagonists.

The glutamate receptor channel subtype that responds to both quisqualate (QA) and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) was expressed in Xenopus oocytes injected with rat cerebral cortex mRNA. Voltage-clamp current responses to QA, AMPA, and glutamate (GLU) exhibited a rapid increase followed by a decrease to a desensitized steady state (DS). Perfusion with high agonist concentrations produced smaller DS responses than perfusion with low concentrations. During the DS, the current was increased by lowering of the concentration of agonist or by application of low concentrations of a competitive antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX). This paradoxical increase of the agonist-induced currents during the DS was also observed in cultured Purkinje cells with another competitive antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). Dose-response curves obtained in oocytes were bell shaped, with a negative slope for high concentrations of QA. DNQX shifted these bell-shaped curves to the right. Together, these results indicate that the agonists are able to reversibly inhibit the AMPA receptor. The classical desensitization model of Katz and Thesleff [J. Physiol. (Lond.) 138:63-80 (1957)] cannot account for our observations.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Effect of imipramine in the "learned helplessness" model of depression in rats is not mimicked by combinations of specific reuptake inhibitors and scopolamine.

Administration of imipramine, which blocks noradrenergic, serotonergic and cholinergic reuptake, to rats for 4 days counteracts the shuttlebox escape failures otherwise seen in rats which have been exposed to inescapable shock (the "learned helplessness" model of depression). The effects of the more selective reuptake inhibitors talsupram (noradrenergic), citalopram (serotonergic) and the anticholinergic compound scopolamine were assessed alone and in combination after acute or 4 days' administration on escape behavior. Their possible synergistic effects when combined with imipramine were also assessed. Talsupram and citalopram were ineffective, whereas scopolamine counteracted the escape failures. Combinations of talsupram, citalopram and a subeffective dose of scopolamine were ineffective. A synergistic effect was only seen when scopolamine was combined with a suboptimal dose of imipramine. Thus, the effect of imipramine on "learned helplessness" might rely partly on its anticholinergic component. However, as an acute high dose of imipramine (25 mg/kg) was ineffective [unlike the acute administration of scopolamine (0.12 mg/kg)], this drug retains a pharmacological effect which is not mimicked by scopolamine alone or by combining the specific reuptake inhibitors with scopolamine.

Animals↗

Effect of nifedipine on the shuttlebox escape deficit induced by inescapable shock in the rat.

The behavioural effect of subchronic treatment with calcium channel antagonists (nifedipine, verapamil) and with imipramine was assessed in rats subjected to inescapable shock (IS). The effect of subchronic treatment with nifedipine and imipramine on specific [3H]nitrendipine ([3H]NDP) binding was investigated in frontal cortex of naive rats and in rats given IS then tested for shuttlebox escape. The rats showed a severe impairment in escape behaviour after IS. Imipramine and nifedipine significantly reduced FR1 and FR2 escape deficits. Verapamil had no effect. A small but significant increase in the number of [3H]NDP binding sites (Bmax) was seen in rats exposed to the shuttlebox escape test independent of a previous exposure to IS. Imipramine had no influence on Bmax in any of the groups. Nifedipine did not affect [3H]NDP binding in naive rats but decreased Bmax in rats subjected to IS and the shuttlebox escape test. The comparable ability of nifedipine and imipramine to reverse the shuttlebox escape deficit induced by IS argues for a possible antidepressant activity of nifedipine. The biochemical data indicate that cortical [3H]NDP binding sites are not correlated to performance in the shuttlebox escape test.

Animals↗

Differential recovery in measures of exploration/locomotion after a single dosage of reserpine in the rat.

Different aspects of exploration/locomotion were studied in rats injected with reserpine (4 mg/kg i.p.) once and in vehicle injected yoked controls. Fifteen different parameters were measured on 7 sessions - on the 1st, 3rd, 5th, 7th, 11th, 15th and 21st postinjectiorn day. The difference scores (the value obtained from the control animal minus the corresponding value from the yoked reserpinized animal) were subjected to nonparametric analysis of variance across sessions. Of the 15 parameters only 6 revealed significant differences between sessions. Furthermore, for those six parameters which exhibited significant differences between sessions the recovery patterns revealed by differences between sessions were dissimilar. It is concluded that what is usually referred to as exploratianflocomotion must be considered apparatus- and procedure-specific and that the measures obtained in different studies should only be compared when identical procedures have been employed. In addition to the measures of exploration/locomotion the rats were subjected to a parallel series of active avoidance sessions in a shuttle-box. Comparing the reserpinized rats impaired active-avoidance aquisiticm to the recovery patterns in the exploratiodlocomotion tests, it can be tentatively concluded that the lack of recovery in the active-avoidance test is not solely due to impaired motoric abilities.

Animals↗

Late aluminum therapy reduces the cellular activities of simple silicosis in the sheep model.

To evaluate the biological effects of aluminum lactate therapy on nodular silicosis, we exposed the tracheal lobe of three groups of sheep containing eight sheep per group to either 11 mg of Al lactate in 100 ml saline (Al group), 100 mg of Minusil-5 in 100 ml saline (Si group), or 100 mg of Minusil-5 in 100 ml saline followed by 11 mg of Al lactate at monthly intervals 4 months after exposure (Si Al-treated group). The lung biological processes were evaluated by sequential lung lavage analyses of cellularity and biochemistry of supernatant and by autopsy analyses of cellularity and biochemistry of supernatant and by autopsy analyses of lung tissue histopathology and quartz content. Al lactate alone did not have any significant effect. Silica exposure produced the silicotic nodules and significant increases on lung lavage of cellularity, enzyme release, surfactant, and glycosaminoglycan accumulations. Al lactate therapy at month 4 after exposure did not decrease the pathological score of disease, but it significantly reduced all markers of cellular hyperactivity. This therapy was associated with a 65% reduction of the quartz retention in lung tissue and might help to prevent long-term progression of the disease process.

Aluminum↗

The lung biological activity of American attapulgite.

Attapulgite is a fibrous mineral industrially consumed at the rate of over a million tons per year but the biological activity of the material is not fully known. To evaluate the in vivo toxicity of the fibrous material, we exposed the tracheal lobe of 16 sheep to a single exposure of either 100 ml saline, 100 mg UICC asbestos fibers in 100 ml saline, 100 mg short asbestos fibers in 100 ml saline, or 100 mg attapulgite in 100 ml saline. The animals were studied by bronchoalveolar lavage (BAL) at Days 2, 12, 24, 40, and 60 and by autopsy at Day 60. In the saline-exposed sheep, BAL and lung histology did not change. In the UICC asbestos-exposed animals, we reproduced the BAL changes previously reported (R. Bégin, M. Rola-Pleszczynski, S. Massé, Y. Berthiaume, and G. Drapeau, 1985, Environ. Res. 36, 389-404). In the short asbestos-exposed sheep, there were no significant BAL changes. In the attapulgite sheep, we found significant and sustained increases in total BAL cells (X2, P less than 0.05), macrophages (X2, P less than 0.05), neutrophils (X5, P less than 0.01), fibronectin (X2-3, P less than 0.05), lactate dehydrogenase (X2, P less than 0.05), beta-glucuronidase (X2, P less than 0.05), but BAL cellularity returned to control levels by Day 60 whereas in the UICC asbestos-exposed sheep, it remained significantly above control. Lung histology demonstrated the characteristic peribronchiolar fibrosing alveolitis in the UICC asbestos-exposed sheep, whereas macrophagic alveolitis with minimal airway distortion was seen in the short asbestos-exposed sheep and in all of the attapulgite-exposed sheep but three which had typical peribronchiolar alveolitis quite similar to that observed in UICC-exposed sheep, but of lower intensity. In conclusion, the study documents that attapulgite is not an inert material for lung tissue; it does produce a macrophagic and neutrophilic alveolitis in the early inflammatory phase of lung reaction with peribronchiolar involvement in some sheep. Whether or not this initial attapulgite induced alveolitis leads to lung fibrosis remains to be evaluated in a longer follow-up study of attapulgite-exposed animals.

Animals↗

Sustained efficacy of aluminum to reduce quartz toxicity in the lung.

In a recent study of the sheep tracheal lobe model, we have demonstrated that surface chemistry modification of quartz by aluminum lactate significantly alters the biological activity of quartz for at least 2 months after exposure. In the present study, we have extended our observations of the biological reaction of the lung tissue to aluminum treated quartz and to untreated quartz, added lung lavage analyses of surfactant and glycosaminoglycans as additional indicators of activity of the quartz-induced lung injury and analyzed lung lavage and tissue retention of the minerals. The tracheal lobe of 8 sheep was exposed to either 11 mg of aluminum lactate in 100 ml saline (Al group), 100 mg of quartz (Minusil-5) in 100 ml saline (Si group) or 100 mg of quartz treated with 11 mg of Al lactate in 100 ml saline (Si-Al group). The 24 sheep were studied by lung lavage at month 9, 0.13, 1, 2, 3, 5, 7, 9, and 10 and by autopsy at month 10. In the Al group, we found no significant change over time, the pathologic score was 0.38 +/- 0.15 and Si undetectable. In the Si group, we found significant sustained increases in total lavage cells, macrophages, lymphocytes, neutrophils, glycosaminoglycans, lactate dehydrogenase, phosphatidylcholine and phosphatidylglycerol. Histologically we found a macrophagic lymphocytic alveolitis with early nodular silicotic lesions; the pathological score was 3.0 +/- 0.8 at month 10 with an average quartz tissue level of 1.4 +/- 0.4 micrograms/mg. In the Si-Al group, all these changes were significantly reduced early and remained so up to 10 months after exposure; the pathological score was 1.1 +/- 0.4 and lung levels of quartz were undetectable. The data thus demonstrated that Al treatment of quartz significantly reduces the biological activity of quartz and increases its clearance with essentially no detectable particle retention in the lung 10 months after exposure.

Aluminum↗

Aluminum lactate treatment alters the lung biological activity of quartz.

Previous studies of surface modification of quartz particles have suggested that the biological activity of silica is at least in part related to its surface properties. In the present study, we exposed the tracheal lobe of 8 sheep to either 100 ml saline (saline group), 100 mg of quartz (Minusil-5) in 100 ml saline (SI group) or 100 mg of Al lactate treated quartz in 100 ml saline (SI-Al group). The 24 sheep were studied by bronchoalveolar lavage at days 0, 12, 24, 40, 60 and by autopsy at day 60. In the saline group, BAL analyses were as previously reported [1]. In the SI group, we found significant and sustained increases in total BAL cells (x 2, P less than 0.05), macrophages and lymphocytes (x 2, P less than 0.05), neutrophils (x 5-10, P less than 0.01), IgG (x 1.2-1.8, P less than 0.05), fibronectin (x 2-3, P less than 0.05), lactate dehydrogenase (x 3, P less than 0.01) and alkaline phosphatase (x 2, P less than 0.05). Histologically, a macrophagic and lymphocytic alveolitis was observed at day 60. In the SI-Al group, these changes were significantly attenuated and in the above parameters, SI-Al group did not differ from saline group after day 24. These data of BAL and histology of the sheep tracheal lobe model document clearly that aluminum lactate treatment alters the biological activity of quartz.

Animals↗