Protective effects of Saccharomyces boulardii CNCM I-745 in an experimental model of NSAID-induced enteropathy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce a broad spectrum of gastro-intestinal adverse effects, including ulceration and bleeding. The pathophysiology of NSAID enteropathy is complex and incompletely understood, but some evidence showed that NSAIDs impair the intestinal barrier and cause a gut dysbiosis. Identifying new treatments aiming to reverse or attenuate NSAID-induced adverse effects would have a significant impact on a high number of patients. The aim of this work is to assess the effects of the probiotic yeast Saccharomyces boulardii CNCM I-745 (Sb) on a model of NSAID-induced enteropathy. Four groups of mice were tested: Control, Indomethacin, Sb, and Sb + Indomethacin. A clinical score was evaluated throughout the experiment. Faecal calprotectin, microbiota and haemoglobin analyses were performed. At the end of the treatments, the small intestine, colon, and caecum lengths, and intestinal permeability were measured. Sections of ileum and jejunum were observed to assess a histological score and ileal cytokines were measured by immunoassay. Indomethacin-treated animals showed an increase in their clinical scores, reflecting a worsening of their general state. Mice co-treated with Sb and indomethacin displayed an improvement of their clinical score in comparison with mice treated with indomethacin alone. Sb prevented the indomethacin-induced shortening of the small intestine and caecum, and significantly attenuated the severity of intestinal lesions. Sb also prevented the increase in faecal calprotectin, reduced faecal haemoglobin, and prevented the increase of intestinal permeability in mice treated with indomethacin. Sb also counteracted the increase of faecal bacteria associated with the pathogenesis of NSAID-enteropathy. In conclusion, our results show a protective effect of Sb in a model of indomethacin-induced enteropathy. Sb improved the intestinal barrier function and exerted a positive action on gut microbiota composition.

[Advance directives in perinatal psychiatry: A parenting aid for women with bipolar disorder?] / Directives anticipées en psychiatrie périnatale : une aide à la parentalité pour les femmes ayant un trouble bipolaire ?

Advance directives in psychiatry (ADP) allow patients to anticipate their requests for care. Their purpose is to promote the acceptation of care, prevent relapses and maintain the autonomy of people with severe and persistent disorders such as bipolar disorder (BD). The risk of relapse is particularly high during the perinatal period. ADPs could be a tool to facilitate care pathway and so maintain mood stability for women with BD during the perinatal period and provide good conditions for child development.

Procedures for risk-stratification of lung cancer using buccal nanocytology.

Lung cancer is the leading cause of cancer deaths in the U.S. with survival dramatically depending on stage at diagnosis. We had earlier reported that nanocytology of buccal cells can accurately risk-stratify smokers for the presence of early and late-stage lung cancer. To translate the technique into clinical practice, standardization of operating procedures is necessary to consistently yield precise and repeatable results. Here, we develop and validate simple, robust, and easily implementable procedures for specimen collection, processing, etc. in addition to a commercially-viable instrument prototype. Results of this work enable translation of the technology from academic lab to physicians' office.

Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue.

Ultrasound-mediated drug delivery is a novel technique for enhancing the penetration of drugs into diseased tissue beds noninvasively. By encapsulating drugs into microsized and nanosized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery to a target site by ultrasound exposure. Traditional in vitro or ex vivo techniques to quantify this delivery profile include optical approaches, cell culture, and electrophysiology. Here, we demonstrate an approach to characterize the degree of nitric oxide (NO) delivery to porcine carotid tissue by direct measurement of ex vivo vascular tone. An ex vivo perfusion model was adapted to assess ultrasound-mediated delivery of NO. This potent vasodilator was coencapsulated with inert octafluoropropane gas to produce acoustically active bubble liposomes. Porcine carotid arteries were excised post mortem and mounted in a physiologic buffer solution. Vascular tone was assessed in real time by coupling the artery to an isometric force transducer. NO-loaded bubble liposomes were infused into the lumen of the artery, which was exposed to 1 MHz pulsed ultrasound at a peak-to-peak acoustic pressure amplitude of 0.34 MPa. Acoustic cavitation emissions were monitored passively. Changes in vascular tone were measured and compared with control and sham NO bubble liposome exposures. Our results demonstrate that ultrasound-triggered NO release from bubble liposomes induces potent vasorelaxation within porcine carotid arteries (maximal relaxation 31%± 8%), which was significantly stronger than vasorelaxation due to NO release from bubble liposomes in the absence of ultrasound (maximal relaxation 7%± 3%), and comparable with relaxation due to 12 µM sodium nitroprusside infusions (maximal relaxation 32%± 3%). This approach is a valuable mechanistic tool for assessing the extent of drug release and delivery to the vasculature caused by ultrasound.

Functional modulation of gamma-aminobutyric acid(A) receptors by etifoxine and allopregnanolone in rodents.

We looked for an interaction between etifoxine and the neurosteroid allopregnanolone at central gamma-aminobutyric acid (GABA(A)) receptors. Etifoxine (2 microM) did not affect the affinity of allopregnanolone (IC(50)=108 nM) for its site in preparations of Sprague-Dawley rat cerebral cortex membranes, as determined by the inhibition of [(35)S] t-butylbicyclophosphorothionate binding, a specific ligand of the GABA(A) receptor chloride channel site. Etifoxine and allopregnanolone were anticonvulsants, blocking the clonic convulsions induced by bicuculline (an antagonist of the GABA(A) receptor) in CD1 mice. A combination of subactive doses of the two compounds showed additive anticonvulsant effects. These results suggest that etifoxine and allopregnanolone bind to distinct putative recognition sites at or near the chloride channel site. Functionally, their binding may have an additive effect by enhancing GABA(A) inhibitory transmission.

Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine.

We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [(35)S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC(50) of 6.7+/-0.8 microM and [(3)H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC(50) of 27.3+/-1.0 microM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 microM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 microM which reflected the post-synaptic potentiation of a small ( approximately 20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl(-) current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 microM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 microM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs.

Phenazone potentiates the local anaesthetic effect of lidocaine in mice.

To justify the inclusion of phenazone, independently of its anti-inflammatory properties, in combination with a local anaesthetic, such as lidocaine, in some ear drop medications, we have studied the effect of this compound on the local anaesthetic activity of lidocaine in an animal model, that of sciatic nerve blockade in mice. Lidocaine and phenazone were tested alone and in combination at various concentrations. The local anaesthetic activity was estimated as the loss of motor activity of the hindlimb after topical injection of the drugs in the region of the sciatic nerve. Lidocaine, at concentrations ranging from 0.03 to 0.25%, induced a concentration-dependent anaesthetic effect. Phenazone alone had no effect at 0.25-1%. When combined, the two compounds acted synergistically. The local anaesthesia induced by lidocaine plus phenazone was significantly more intense and longer lasting than that induced by lidocaine alone. Phenazone enhanced the potency of lidocaine in this animal model. It is suggested that the potentiated local anaesthetic effect of the combination may be partly due to enhanced local bioavailability of lidocaine.

Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex.

This study examined the nature of the interactions of etifoxine, an anxiolytic and anticonvulsant compound, with the GABA(A) receptor/chloride channel complex. In membrane preparations of Sprague-Dawley rat cerebral cortex, etifoxine competitively inhibited the binding of [35S]t-butylbicyclophosphoro-thionate (TBPS), a specific ligand of the GABA(A) receptor chloride channel site. In vivo studies demonstrated an anticonvulsant effect of etifoxine (50 and 75 mg/kg, i.p.) against the clonic convulsions induced by TBPS in CD1 mice. Flumazenil (10 and 40 mg/kg, i.p.), an antagonist of benzodiazepine sites at GABA(A) receptors, had no effect on the action of etifoxine. These findings suggest that etifoxine exerts its effect by interacting with the Cl- channel of GABA(A) receptors and probably by facilitating GABAergic inhibition.

Citrulline malate limits increase in muscle fatigue induced by bacterial endotoxins.

Citrulline malate is known to improve performance in weakened muscles. The present experiment was designed to test the hypothesis that citrulline malate can limit the effect of endotoxins on muscle fatigability. Endotoxemia was induced in rats by injection of lipopolysaccharides from Klebsiella pneumoniae. Resistance to fatigue was quantified by measuring tension production during repetitive electrical stimulation of the isolated epitrochlearis muscle. Oral treatment by citrulline malate was found to increase resistance to fatigue in infected rats, whereas twitch tension was not modified. This demonstrates the efficacy of citrulline malate for limiting an increase in muscle fatigue elicited with bacterial endotoxins.

Effects of citrulline malate on bacterial lipopolysaccharide induced endotoxemia in rats.

The administration of endotoxins to rats as lipopolysaccharides (LPS) induces a state of exhaustion, in which the main symptoms are febrile hyperthermia, reduced food intake, decreased body weight, and reduced muscle performance in treadmill tests. Underlying the physiological and behavioral disturbances due to the LPS is the activation of macrophages that release cytokines (interleukin-1, tumor necrosis factor a) and NO. The cellular responses are intended to maintain homeostasis. Provision of citrulline as citrulline malate (CAS 54940-97-5, Stimol), an antifatigue substance, improved muscle performance, but had no effect on the body temperature or on the body weight of these animals weakened by LPS. The presence of citrulline in the NO synthesis pathway, or its participation in the speeded up elimination of ammonia and lactates, the main products of muscle metabolism, might explain the effects of citrulline malate in rats treated with LPS.

Endotoxins modify muscle fatigue characteristics.

To test the hypothesis that endotoxins can directly modify muscle fatigue characteristics, in vitro experiments were performed on rat muscles 48 hours after injection of lipopolysaccharides (LPS) from Klebsiella pneumoniae. Resistance to fatigue was quantified by measuring tension production during repetitive electrical stimulation of the isolated epitrochlearis muscle. LPS treatment did not significantly modify initial force production whereas fatigability of the muscle was increased. This in vitro preparation should be used for testing antifatigue drugs.

Electromyographic activity and noradrenaline content of the rabbit oviduct under different hormonal states.

Spontaneous electromyographic (EMG) activity of the oviduct recorded in vivo in untreated, estrogen-treated, and progesterone-treated castrated rabbits was found to exhibit two main patterns: short spike bursts lasting 1-10 s and long trains of action potentials lasting several minutes, which constituted the major component of EMG activity. After estrogen treatment, both wet weight and noradrenaline (NA) content of the castrated rabbit oviduct were enhanced mainly at the ampullary-isthmic junction; long trains of discharges were significantly shorter (2.0-2.7 min vs 3.6-4.6 min) and appeared at more frequent intervals (9.8-12.2 min vs 14.2-22.6 min). After progesterone treatment, spontaneous EMG activity was not significantly different from that in untreated castrated rabbits (as was the NA content) except at the ampullary-isthmic junction. NA injection elicited a stimulatory response of the oviduct lasting 1-7 min in the three hormonal states. Phentolamine strongly depressed spontaneous EMG activity but the inhibition was more transient in castrated rabbits than in estrogen-treated and progesterone-treated animals. Propranolol had no effect on spontaneous EMG activity. These data and the high NA concentrations found in all parts of the isthmus support the hypothesis that adrenergic innervation plays a role in the organization of oviductal motility in the rabbit.

Behavioral effects of intrahippocampal injections of clonidine, yohimbine and salbutamol in the rat.

Intrahippocampal injections of adrenergic drugs, clonidine (an alpha 2-agonist), yohimbine (an alpha 2-antagonist), and salbutamol (a beta 2-agonist) were performed in the awake rat. The injection of a high dose of clonidine caused a depression in locomotion in the open-field. Yohimbine partially antagonized the clonidine-induced hypomotility. The intrahippocampal injection of salbutamol had no effect on ambulatory behavior of the rat. These results suggest that the role played by the anterodorsal hippocampus in modifying behavior in novel situations is dependent on the specific sub-population of adrenoceptors that is stimulated.

Preovulatory injection of estradiol-17 beta: effect on noradrenaline activity in different parts of the rabbit oviduct.

This paper compares noradrenaline content in the different parts of the oviduct in rabbits receiving or not a dose of estradiol-17 beta 24 h before human chorionic gonadotropin (HCG) and killed 60 h post HCG. 3,4-Dihydroxyphenylalanine assays were carried out in the oviduct after aromatic L-amino acid decarboxylase was inhibited by m-hydroxybenzylhydrazine (NSD 1015) in the same experimental conditions. Pauerstein et al. (1974) have shown that an intramuscular injection of 250 micrograms of estradiol-17 beta in rabbits 24 h before intravenous injection of 100 IU of HCG delays ovum transport at the ampullary-isthmic junction. The extent of this noradrenergic innervation suggested that estradiol could act at least partially through the noradrenergic systems. Our results show that estradiol-17 beta increased oviduct weight by water retention without modifying either the tyrosine hydroxylase activity or the noradrenaline content in any part of the oviduct and that, consequently, the estrogen-induced "tube locking" of ova was not mediated through the noradrenergic processes.

A comparative study of the behavioral effects of the locus coeruleus and the dorsal noradrenergic bundle lesions in the rat.

The effects of bilateral lesions of the dorsal noradrenergic bundle (DB) or of the locus coeruleus (LC) on the rat's behavior in different anxiogenic behavioral situations have been studied. The DB rats defecate less but ambulate more than shams in the open-field (O.F.); these data suggest a decrease in the reactivity of these animals to novelty. Furthermore, the LC rats have a behavior identical to that of shams in the O.F. We note moreover that the DB rats do not habituate to a novel stimulus. During the Henderson test, the behavioral inhibition of all lesioned animals seems to be less important than that of shams. These results are discussed in relation to existing hypotheses of the DB function. The lesions of DB induce a decrease in the noradrenaline (NA) cortical level and in the catecholamines level in hypothalamus. The lesions of LC produce 30% loss of forebrain NA. These results reveal a discrepancy between the effects induced by the lesioning of DB fibers and those produced by lesions of LC, which originate in the DB. The presence of non-noradrenergic elements, fibers of passage, which do not travel with the DB fibers or terminals in the LC region may be elements for interpretation.

Behavioral effects of lesions of the central noradrenergic bundles in the rat.

Rats with bilateral lesions of the dorsal noradrenergic bundle (DB) or of the ventral noradrenergic bundle (VB) were studied in different behavioral test situations. All lesioned animals defecate less than sham operated animals in the open-field (OF) or in the conditioning apparatus described by Henderson [16]. These data suggest a decrease of emotional reactivity in lesioned animals. However, the DB rats' level of exploration was higher than that of VB rats. No effect on the amplitude of the startle response has been shown after lesioning. The lesions of the dorsal noradrenergic bundle induce a decrease in cortical noradrenaline hypothalamic catecholamines. The lesions of the ventral noradrenergic bundle induce a decrease in hypothalamic catecholamines without change in the cortex. These results do not support the postulation [22] that the dorsal bundle and the ventral bundle play an opposite role in behavior. Yet, a selective participation of each bundle is suggested in modulating responses to novel environments and anxiogenic situations.