Biomedical subjects

F Clostre

Publications and source records attributed to F Clostre.

At least 19 recordsLinked to original sources

PubMed2006

[A Nematode Nobel Prize: Caenorhabditis elegans].

The Nematode Caenorhabditis elegans (C. elegans) is an established model increasingly used for studying human disease pathogenesis. C. elegans models are based on the mutagenesis of human disease genes conserved in this Nematode or on the transgenesis with disease genes not conserved in C. elegans. Genetic examinations will give new insights on the cellular and molecular mechanisms that are altered in some neurodegenerative diseases like Duchenne's muscular dystrophy, Huntington's disease and Alzheimer's disease. C. elegans may be used for primary screening of new compounds that may be used as drugs in these diseases.

Alzheimer Disease↗

PubMed2001

[Mitochondria: recent pathophysiological discoveries and new therapeutic perspectives].

Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases.

Animals↗

PubMed1999

[Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year 2000].

EGb 761 is a standardized extract of dried leaves of Ginkgo biloba containing 24% ginkgo-flavonol glycosides, 6% terpene lactones such as ginkgolides A, B, C, J and bilobalide. Its broad spectrum of pharmacological activities allows it to be in adequacy to the numerous pathological requirements--hemodynamic, hemorheological, metabolic--which occur in cerebral, retinal, cochleovestibular, cardiac or peripheral ischemia. Moreover, EGb 761 has direct effects against necrosis and apoptosis of neurons and improves neural plasticity as evidenced in vestibular compensation. At the molecular and the cellular levels, some evidence obtained with animal models indicates that EGb 761 can interact as a free radical-scavenger and a inhibitor of lipid peroxidation with all, or nearly all reactive oxygen species; maintains ATP content by a protection of mitochondrial respiration and preservation of oxidative phosphorylations; exerts arterial and venous vasoregulator effects involving the release of endothelial factors and the catecholaminergic system. Moreover, EGb 761 regulates ionic balance in damaged cells and exerts a specific and potent Platelet-activating factor antagonist activity. Numerous well-controlled clinical studies, realized in Europe and in USA, have revealed that EGb 761 is an effective therapy for a wide variety of disturbances of cerebral function, ranging from cerebral impairment of ischemic vascular origins (i.e. multi infarct dementia), early cognitive decline to mild-to-moderate cases of the more severe types of senile dementias (including Alzheimer's disease) or mixed origins (i.e. psychoorganic origin). Improvement of signs and symptoms have been demonstrated for cognitive functions, particularly for memory loss, attention, alertness, vigilance, arousal and mental fluidity. Some clinical studies have showed that EGb 761 treatment may improve the capacity of geriatric patients to cope with the stressful demands of daily life. The explanation is a dual stress-alleviating action of EGb 761: its facilitates behavioral adaptation to stress and may decrease the excess of cortisol release to stress. Moreover, EGb 761 shows a specific neuroprotective effects to hippocampic cells. Regarding the visual system, experimental studies have shown that EGb 761 can inhibit or reduce the functional retinal impairments resulting from ischemia-reperfusion, photo-degeneration, diabetic or proliferative retinopathy. Clinical studies have revealed that EGb 761 may be useful in treating visual activity impairments and damages to the visual field associated with chronic cerebrovascular insufficiency, senile macular degeneration and diabete mellitus. Regarding the vestibular and auditory systems, experimental and clinical studies have shown the efficacy of EGb 761 in treating hypoacusis, tinnitus, vertigo, dizziness and other symptoms of vestibulocochlear disorders. At least, adequatly controlled studies in patients with peripheral arterial occlusive disease have provided good evidence for therapeutic efficacy in intermittent claudication. The future of EGb 761 is undoubtedly in the promise in slowing the progression of Alzheimer's disease. Indeed, two recent american clinical studies have shown the efficacy and safety of EGb 761 in patients with mild to severe Alzheimer's disease and multi-infarct dementia. In clinical terms, progression of symptoms was delayed by approximately 6 months. Actually new clinical studies are undertaken in USA and Europe. At the dawn of the third millenium (the Sixth for Ginkgo biloba) we propose a state of art about it.

Animals↗

PubMed1997

Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging.

A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.

Aging↗

PubMed1994

[Microcirculation and rheology].

Microvessels, especially in the skin and muscles are organized in functional units. These units are controlled by the adrenergic system and hormones but also have autonomous metabolic and myogenic regulatory systems independent of vasomotion. Microcirculatory blood flow is affected by special rheologic properties: a low arteriolar haematocrit rises to the systemic level in the venules. The flow rate in the venules is low, and together with the raised haematocrit, explains the microvenular sensitivity to hyperviscosity. Capillarovenular microangiopathy, recently described by standard and fluorescent capillaroscopy, develops during chronic venous insufficiency. The capillary loops appear dilated and knotted together with fibrous deposits and pericapillary oedema. Venous hyperpressure is the cause of this microangiopathy. Together these phenomena disrupt normal haemodynamics and physiology of the microcirculatory unit: baseline hyperhaemia, lowered vasomotor and vasomotion reactivity, development of rheologic disorders (haemoconcentration, hyperfibrinogenaemia, erythrocyte agregation) and decreased fibrinolysis. Modifications in the transcapillary exchange is related to hypoxia and is aggravated by depressed lymphatic drainage. The main consequence is oedema. Inflammation, a characteristic of these microangiopathies could occur when the endothelium is activated by the hypoxia. The classical mediators of inflammation would activate interactions between the different cells: endothelium, granulocytes, monocytes and platelets. Several pharmacological models have been developed for the analysis of these data including exploration of the permeability and capillary resistance and rheological analysis. Objective observation of the microangiopathy with capillaroscopy, together with modern haemodynamical, biological and pharmacological methods are essential for a better understanding of microvascular disorders in chronic venous insufficiency.

Capillary Permeability↗

PubMed1994

[Functions of the endothelium].

The venous endothelium, acting as an interface between the blood and the layer of smooth muscle cells, plays a major role in many essential functions of vessel physiology. The endothelium prevents and inhibits pathological activation of the coagulation system and plays an active role in the regulation of venous tone. Mediators include the prostacyclin which has vasodilating and antiagregating properties and nitric oxide (NO), a vasodilator and inhibitor of thrombosis, adhesion and cellular proliferation. To maintain endothelial integrity and tissue cohesion, endothelial cells express adhesion factors which regulate cell to cell and cell to extracellular matri interactions. Finally, the endothelium plays a role in vasotrophism by synthesizing, or activating growth factors which act directly on cell renewal of the endothelium itself and proliferation of adjacent tissues. Thus, the venous endothelium cannot be considered simply as a biologically inert barrier but rather as an active cell layer capable of intercell signalling and interactions constantly modified by the pathophysiological environment.

Blood Coagulation Factors↗

PubMed1992

Prevention by Ginkgo biloba extract (EGb 761) and trolox C of the decrease in synaptosomal dopamine or serotonin uptake following incubation.

Prolonged incubation of synaptosomes in Krebs-Ringer oxygenated medium in the presence of ascorbic acid (10(-4) M) led, after 20 min, to a decrease in [3H]dopamine (DA) (synaptosomes prepared from the striatum) and [3H]serotonin (5HT) (synaptosomes prepared from the cortex) uptake. The decrease was progressive and uptake was virtually abolished after a 60 min incubation period. A concentration-dependent (from 5 x 10(-6) M) role of ascorbic acid in the decrease of [3H]DA or [3H]5HT uptake was demonstrated. This decrease was potentiated by Fe2+ ions and prevented by the ferrous chelating agent desferrioxamine. Thus, the progressive decrease in synaptosomal uptake of either [3H]DA or [3H]5HT could depend on the generation of free radicals by the association of ascorbic acid with Fe2+ ions. The decrease in synaptosomal uptake was prevented, in a concentration-dependent manner, by the Ginkgo biloba extract EGb 761 (4-16 micrograms/mL) and the vitamin E analog trolox C (10(-4) M). The terpenic fraction of EGb 761, Bn 52063 (up to 0.5 microgram/mL), did not prevent the reduction of [3H]amine uptake. In contrast, the flavonoidic fraction, Cp 202, was effective (from 1 microgram/mL) and its efficacy was shared by the flavonoid quercetin (from 0.1 microgram/mL). The prolongation of the ability of synaptosomes to take up [3H]amine elicited by EGb 761, in particular its flavonoidic fraction, as well as by trolox C could be due to their free radical scavenger properties.

Animals↗

PubMed1992

The Ginkgo biloba extract, EGb761, increases synaptosomal uptake of 5-hydroxytryptamine: in-vitro and ex-vivo studies.

The Ginkgo biloba extract (EGb 761) added to a synaptosomal fraction prepared from mice cerebral cortex modified [3H]5-hydroxytryptamine ([3H]5-HT) uptake in a biphasic manner. Between 4 and 16 micrograms mL-1 EGb 761 increased significantly the [3H]5-HT uptake (maximum + 23%). A similar increase was also obtained when synaptosomes were prepared from the cortex of mice treated orally with EGb 761, either acutely (100 mg kg-1, 14 h and 2 h before death) or semi-chronically (2 x 100 mg-1 kg daily for 4 consecutive days). The in-vitro increase in [3H]5-HT uptake induced by EGb 761 was not observed in the presence of 10(-6) M clomipramine, a 5-HT-uptake inhibitor. EGb 761 did not increase [3H]dopamine uptake by synaptosomes prepared from striatum of mice. We investigated different fractions of EGb 761 in order to determine the compounds inducing the increase in [3H]5-HT uptake. The BN 52063 extract (corresponding to the EGb 761 devoid of flavonoid substances) did not increase [3H]5-HT uptake. The Cp 202 extract (corresponding to the EGb 761 devoid of terpenic substances and containing mostly flavonoid substances) increased [3H]5-HT uptake. Among the flavonoids, quercetin has been tested and had no effect on the [3H]5-HT uptake. Since at the usual therapeutic doses of EGb 761, the effective concentrations of the components responsible for this increase are likely to be reached in the brain, one may suggest that this effect could contribute to the therapeutic effect of EGb 761.

Animals↗

PubMed1991

Platelet activating factor antagonists interact with GABAA receptors.

Platelet activating factor (PAF) is ubiquitous in mammals, and may have multiple functions in the central nervous system. Triazolobenzodiazepine compounds are active both at the GABAA receptor and as PAF antagonists. To investigate whether PAF antagonist activity is involved in the actions of triazolobenzodiazepines, we examined effects of two non-benzodiazepine PAF antagonists on binding and function at the GABAA receptor. The gingkolide terpene, BN 52021 and the dioxolane-based compound BN 52115 had no effect on benzodiazepine binding or chloride channel binding in cortical membrane preparations. However, chloride uptake into cortical synaptoneurosomes was enhanced with 1 microM BN 52021 but not 1 microM BN 52115. The effect of BN 52021 was prevented by 1 microM flumazenil. PAF antagonists appear to augment GABAA receptor function without affecting binding.

Animals↗

PubMed1990

Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP.

In mice implanted subcutaneously with osmotic minipumps releasing the neurotoxic agent N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days (105 micrograms h-1/mouse) (approximately 100 mg kg-1 day-1) a significant reduction (approximately 25%) in the striatal dopaminergic nerve endings was observed. This neurotoxic effect was prevented by the semi-chronic ingestion of a Ginkgo biloba extract for 17 days (GBE 761, approximately 100 mg kg-1 day-1). The high concentrations (approximately 1 g L-1) at which GBE 761 in-vitro either prevented the uptake of [3H]dopamine by synaptosomes prepared from striatum, or prevented the specific binding of the pure dopamine uptake inhibitor [3H]GBR 12783 to membranes prepared from striatum suggests that the prevention of the MPTP neurotoxicity does not depend on an inhibition of the MPTP uptake by dopamine neurons. This is also suggested by the lack of prevention of the in-vitro striatal binding of [3H]GBR 12783 administered i.v. at a tracer dose, in mice pretreated for 8 days with GBE 761 (100 mg kg-1 p.o.) and receiving a supplementary gastric administration of GBE 761 (100 mg kg-1) 1 h before testing. Similar treatment with GBE 761 did not modify the toxicity for dopamine neurons of 6-hydroxydopamine (20 micrograms) directly injected into the striatum of rats.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Role of endothelium on phenylephrine-triggered contractile events in aorta of spontaneously hypertensive rats.

The ability of basal release of endothelium derived relaxing factor (EDRF) to alter contractile events in phenylephrine (PE)-triggered contraction was tested on ring segments of the thoracic aorta removed from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In normal medium, PE (1 microM) elicited similar whole contractions in endothelium denuded arteries of SHR and WKY. The presence of endothelium only reduced the WKY response. On aorta incubated in a Ca2+ free-medium, PE (1 microM) induced an initial phasic contraction due to intracellular Ca2+ release. This was followed by a tonic contraction after Ca2+ (2.5 mM) was restored to the bath. This sustained contraction was dependent on extracellular calcium influx. Identical phasic and tonic contractions were observed in endothelium denuded rings of SHR and WKY. However, the presence of endothelium only reduced the sustained contraction of WKY arteries. When experiments were carried out in medium containing D600 (1 microM), the presence of endothelium diminished the whole contraction of both SHR and WKY rings whereas the sustained but not the phasic contractions of WKY was also inhibited. This inhibitory effect of endothelium on WKY sustained contraction was significantly higher in the presence of D600. The calcium antagonist reduced both the whole and the tonic contractions of all preparations but was ineffective on the phasic one. The D600 inhibitory action on the sustained contraction was more pronounced in denuded SHR rings than in the corresponding WKY arteries. Thus it is concluded that there is a basal influence of endothelium in both SHR and WKY. Under our conditions, the endothelial function inhibited the extracellular Ca2+ influx and especially the part of Ca2+ influx insensitive to D600. This part of Ca2+ influx is diminished in SHR and thus the efficacy of endothelium products (e.g. EDRF) is reduced in this strain.

Animals↗

PubMed1989

Effects of atrial natriuretic factor (ANF) on phenylephrine-triggered intra- and extracellular calcium dependent contraction in rat aorta.

1. The ability of atrial natriuretic factor (ANF) to alter the different Ca++ events in phenylephrine (PE)-triggered contraction was tested on isolated rat aorta. Isometric contraction of endothelium-free rat aortic ring was recorded in Ca++ free medium containing 1 mM EGTA. 2. PE (1 microM) induced a phasic contraction and a sustained contraction following addition of Ca++ (2.5 mM) to the medium. The phasic contraction is due to intracellular Ca++ release whereas the sustained one is dependent on extracellular Ca++ influx. The Ca++ antagonist D600 (1 microM) reduced by 39% the sustained contraction without affecting the phasic one. 3. ANF (0.3-3 nM) reduced both contractions, but spasmodic contractions were observed during the sustained phase. A similar effect was noted with sodium nitroprusside (NaNP; 10-100 nM) and forskolin (1 microM) but not with prazosin (1 nM). 4. When D600 was added to the medium either before or after the initial contraction, the spasmodic contractions were completely abolished. Nifedipine (0.1 microM) had a similar effect when added during the sustained phase, while in contrast, addition of the Ca++ agonist BAY K8644 (0.1 microM), increased the frequency of the spasmodic contractions. 5. It can be concluded that in rat aorta ring, PE induces Ca++ release and Ca++ influx via receptor linked channels and potential dependent channels. ANF, NaNP but also forskolin inhibit both Ca++ release and Ca++ influx via receptor linked channels, while unlike prazosin, these agents are less effective in preventing Ca++ influx via potential dependent channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

Endothelin and Ca++ agonist Bay K 8644: different vasoconstrictive properties.

The mechanism of vasoconstriction induced by endothelin was investigated in rat isolated aorta in comparison with the Ca++ agonist, Bay K 8644. Endothelin (EC50 = 4 nM) induced a slow and sustained contraction in control medium whereas the one elicited by Bay K 8644 (EC50 = 14 nM) necessitating a partly K+ depolarized medium was fast with superimposed rhythmic contraction. By opposition with Bay K 8644, endothelin contraction was not inhibited by the calcium antagonists (1 microM), nifedipine, diltiazem and D 600, and substantially persisted in Ca++ free medium or after depletion of intracellular Ca++ by phenylephrine (1 microM). These data show that endothelin does not act as an activator of potential dependent Ca++ channels but probably through specific receptor(s) as suggested by its mode of vasoconstriction.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

Effects of the specific platelet-activating factor antagonists, BN 52021 and BN 52063, on various experimental gastrointestinal ulcerations.

Platelet-activating factor (PAF) has been shown recently to induce gastrointestinal damage similar to that evoked by endotoxin, suggesting that the autacoid could be implicated in other types of gastrointestinal damage. Thus, the effects of BN 52021 and BN 52063, two specific PAF antagonists, were investigated in various experimental models of gastrointestinal damage in rats. BN 52021 and BN 52063, markedly reduced both the PAF- and endotoxin-induced alterations of the mucosa, suggesting a role for the autacoid in the latter process. BN 52021 and another unrelated PAF antagonist, triazolam, partially reduced the restraint-stress-induced gastric damage in young female, but not male, rats. Similar partial protection was obtained in rats with ethanol-induced gastric damage. In contrast with atropine and ranitidine, BN 52021 did not affect the gastric hypersecretion in pylorus-ligated rats nor the aspirin-induced gastric ulcerations. The present results indicate that PAF plays a major role in the gastric damage induced by endotoxin and may also partially contribute to the gastric lesions induced by ethanol and stress. The results suggest that there is a potential therapeutic use for PAF antagonists in certain types of gastrointestinal lesions in man.

Animals↗

PubMed1988

Antihypertensive profile of cicletanine, a furopyridine derivative: comparison with captopril, indapamide and prazosin.

The effects of cicletanine were compared with those of three other antihypertensive drugs: prazosin, a highly selective alpha 1 antagonist, captopril an angiotensin converting enzyme inhibitor and indapamide a diuretic antihypertensive agent, on young stroke-prone SHR rats with high salt diet; furthermore, vascular reactivity to cicletanine was studied on isolated rat aorta. At an equal dose (30 mg/kg per os) all the drugs prevent the onset of hypertension with the same intensity. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on diuresis and electrolyte excretion occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the anti-hypertensive effect. One of the possible mechanisms of the antihypertensive effects of cicletanine could be due to a direct action of the drug on the vascular wall. This vascular impact could be an interaction with the alpha-adrenoceptor system (apparent pA2 cicletanine = 5.12) or a decrease in the vascular spasmogenic response whatever agonist was studied.

Animals↗

PubMed1988

Effects of BN 52063 and other agents inhibiting platelet-activating factor-induced contractile responses in rat portal vein.

Platelet-activating factor (PAF-acether) is a potent agonist (EC50: 3.2 x 10(-8) M) of isolated rat portal vein. BN 52063 (composed of BN 52020, BN 52021 and BN 52022; molar ratio 2:2:1) specifically inhibits PAF-acether (10(-7) M) induced tone (IC50: 3.9 x 10(-5) M). Salbutamol (IC50: 3.1 x 10(-7) M), forskolin (IC50: 3.1 x 10(-6) M) and theophylline (IC50: 2.25 x 10(-4) M) are also effective in inhibiting PAF-acether-induced contractile responses and all excepting forskolin, show a certain specificity in this action. The basal myogenic activity of the rat portal vein is dose-dependently decreased by salbutamol (IC50: 1.2 x 10(-7) M), forskolin (IC50: 2.6 x 10(-6) M) and theophylline (IC50: 2.3 x 10(-4) M) whereas BN 52063 has no effect. The data suggest that rat portal veins possess specific PAF-acether receptors sensitive to BN 52063 and that PAF-acether effects could be inhibited by compounds which can bypass these putative receptors and modulate cAMP levels.

Albuterol↗

PubMed1988

Comparison of cicletanine with other antihypertensive drugs in SHR-SP models.

The effects of cicletanine were compared with those of four other antihypertensive drugs (prazosin, a highly selective alpha 1 antagonist; captopril, an angiotensin-converting enzyme inhibitor; indapamide, an antihypertensive diuretic; and hydrochlorothiazide, a purely diuretic agent) on young stroke-prone SHR rats with high-salt diet. All the drugs except hydrochlorothiazide prevented the onset of hypertension. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on cardiac hypertrophy and diuresis occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the antihypertensive effect. Renal hypertrophy was also decreased significantly by cicletanine at a dose of 100 mg/kg.

Animals↗

PubMed1988

In vitro cardiovascular antihistamine properties of cicletanine in comparison with diphenhydramine.

Cicletanine (CIC) (pA2: 7.0) was found to be as potent as diphenhydramine (DIPH) (pA2: 7.2) in competitively inhibiting histamine-induced contraction of isolated rabbit aorta. Both CIC (pA2: 7.3) and DIPH (pA2: 7.5) similarly shifted histamine-induced endothelium-dependent relaxation of isolated rat aorta to the right. The similarity of results (in terms of pA2 values) indicates that in spite of their opposite responses on vascular tone, the H1 receptors on rabbit and rat aortae may be similar. DIPH was found to be as potent as cocaine in potentiating the chronotropic action of noradrenaline on isolated right atria, whereas CIC was without effect. The ability of DIPH to inhibit the noradrenaline uptake at the neuronal membrane seems to be independent of its H1-receptor antagonism potency. Finally, the furopyridine framework of CIC does not elicit the cocaine-like activity of the oxyethylamine residue of DIPH.

Animals↗