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International audience; Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1–casein hydrolysate and Gabolysat®) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut–brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.

Background Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant ovarian cancers. To correct the unfavorable intrinsic physico-chemical properties of this BCS II drug, a formulation strategy was implied in the drug discovery step. Pyridoclax-loaded nanoemulsions (NEs) were developed to permit its preclinical evaluation. Results The resulting nanoemulsions displayed a mean size of about 100 nm and a high encapsulation efficiency (>95%) at a drug loading of 2 wt%, enabling a 1,000-fold increase of the Pyridoclax apparent solubility. NEs have enabled a sustained release of the drug as assayed by a dialysis bag method. In addition, anti-tumor effects of the Pyridoclax-loaded nanoemulsions (PNEs) showed a 2.5-fold higher activity on chemoresistant ovarian cancer cells than free Pyridoclax. This effect was confirmed by a drastic increase of caspase 3/7 activation from 10 µM PNEs, as newly objectified by real time apoptose imaging. The Pyridoclax bioavailability was kept unchanged after encapsulation in nanoemulsions as determined in a mice model after oral administration. Conclusion Thus, NEs should permit valuable Pyridoclax oral administration, and valorization of this promising anticancer drug by maintaining its original anticancer activity, and by reducing the Pyridoclax therapeutic concentration.

International audience

Recent data suggest that 5-HT7 receptors (5-HT7R) are involved in memory processes and, particularly, those related to novelty-induced arousal, even though this remains so far speculative and controversial. In order to assess the role of 5-HT7R in episodic-like memory, mice were administered 5-carboxamidotryptamine (5-CT, a 5-HT1A/1B/1D/7R agonist) and/or SB-269970 (a selective 5-HT7R antagonist) immediately after the acquisition session of the novel object recognition test. The object recognition test was performed in order to assess the effects of modulation of 5-HT7R during consolidation phase on episodic-like memory performances in mice. A protocol including 3 days of familiarisation to the apparatus has been realised in order to decrease the effect of novelty-induced arousal. With a 2-h delay, SB-269970 (3 and 10 mg/kg, administered subcutaneously) impaired the discrimination of the novel object. With a 4-h delay, while control mice were not able to discriminate the novel object, mice treated with 5-CT (1 mg/kg) showed a significant discrimination. This promnesic effect with a long delay is effectively mediated by 5-HT7R activation since it was blocked by SB-269970 (10 mg/kg), but not by WAY-100135 (10 mg/kg) or by GR-127935 (10 mg/kg). These data suggest that 5-HT7R tonically modulates cognitive processes involved in consolidation performances in object recognition. Therefore, 5-HT7R could be a promising target to treat memory dysfunctions (especially episodically related deficits) related to normal or pathological ageing.

International audience; 5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer's disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits

A variety of 3-(2-nitro)phenylpropanamide derivatives (III) (20 examples) are synthesized and screened for their peripheral analgesic activities on acetic acid-induced writhing in mice.

A series of substituted 6-nitrophenylpropanamide derivatives (1-20) were synthesized using either the TDAE strategy or classical organic reactions. All these compounds were characterized by fusion point, (1)H NMR, (13)C NMR, elemental analysis or mass spectrometry data. Because of their structural analogy with recently published compounds possessing antinociceptive properties, our derivatives were screened for peripheral analgesic activities on acetic acid-induced writhing in mice. Compound 13 showed the best result at 100 μmol/kg ip (50% inhibition vs 59% for aspirin). This antinociceptive activity was maintained after oral administration (40% inhibition vs 31.6% for aspirin). Both hot-plate and actimetry-based tests were non-significant suggesting the analgesic activity of 13 linked to a peripheral mechanism.

International audience; Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT(4)R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also administered. Activation of 5-HT(4)R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.