High-content multimodal analysis supports the IL-7/IL-7 receptor axis as a relevant therapeutic target in primary Sjögren's syndrome.

Objective: While the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology.

Methods: An IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aβ) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound.

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

Introduction: S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms.

Methods: For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable AD at mild to moderate stages (a Mini-Mental State Examination score of 24-15 inclusive) and exhibiting depressive symptoms (Cornell Scale for Depression in Dementia [CSDD] ≥ 8) were recruited in twelve countries and randomized to 3 doses of S47445 (5-15-50 mg) or placebo. The primary end point was the change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score at week 24.

S 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice.

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway).

Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.

S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms.

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor's (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity.

The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice.

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are small molecules that decrease deactivation of AMPARs via an allosteric site. These molecules keep the receptor in an active state. Interestingly, this type of modulator has been proposed for treating cognitive decline in ageing, dementias, and Alzheimer's disease (AD).

Upregulation of neurotrophins by S 47445, a novel positive allosteric modulator of AMPA receptors in aged rats.

At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1-3-10mg/kg, p.o.

Calpain product of WT-CRMP2 reduces the amount of surface NR2B NMDA receptor subunit.

The brain is particularly vulnerable to ischaemia; however, neurons can become tolerant to ischaemic insult. This tolerance has been shown to involve activation of NMDA receptors, but its mechanisms have not yet been fully elucidated. Using a preconditioning protocol, we show that neurons surviving to a transient NMDA exposure become resistant to the glutamatergic agonist.

Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain.

CRMP1, CRMP2, and CRMP5 have been identified as cytosolic proteins relaying semaphorin 3A signalling, one of the molecular cues conducting axon and dendrite growth and guidance. They are highly expressed during brain ontogenesis, but, because of their lower levels in the adult, their distribution in the mature brain is poorly documented. By using specific antibodies, we investigated the cellular distribution of these CRMPs in different adult brain structures and in neural cell cultures with a special focus on the splice variants CRMP2A and CRMP2B.