Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the chaperone protein.

The aggregation of Amyloid- (A) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with A species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the receptor chaperone and as agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the receptor.

Convolamine, a tropane alkaloid extracted from Convolvulus plauricalis, is a potent sigma-1 receptor-positive modulator with cognitive and neuroprotective properties.

Background And Aim: By using an in vivo phenotypic screening assay in zebrafish, we identified Convolamine, a tropane alkaloid from Convulvus plauricalis, as a positive modulator of the sigma-1 receptor (S1R). The wfs1ab zebrafish larva, a model of Wolfram syndrome, exhibits an increased visual-motor response due to a mutation in Wolframin, a protein involved in endoplasmic reticulum-mitochondria communication. We previously reported that ligand activating S1R, restored the cellular and behavioral deficits in patient fibroblasts and zebrafish and mouse models.

Restorative effects of probiotics on memory impairment in sleep-deprived mice.

Background: Insufficient sleep is a serious public health epidemic in modern society, impairing memory and other cognitive functions. In this study, partial sleep deprivation (SD) was used to induce cognitive impairment in mice to determine the effects of probiotics on subsequent cognitive deficits.

Methods: Lp-115 (Lp-115), Lpc-37 (Lpc-37), subsp.

Efficacy of THN201, a Combination of Donepezil and Mefloquine, to Reverse Neurocognitive Deficits in Alzheimer's Disease.

Donepezil (DPZ) is an acetylcholinesterase inhibitor used in Alzheimer's disease to restore cognitive functions but is endowed with limited efficacy. Recent studies pointed out the implication of astroglial networks in cognitive processes, notably via astrocyte connexins (Cxs), proteins involved in gap junction intercellular communications. Hence, we investigated the impact on cognition of pharmacological or genetic modulations of those astrocyte Cxs during DPZ challenge in two rodent models of Alzheimer's disease-like memory deficits.

In Vitro and In Vivo Neuroprotective Effects of Etifoxine in β-Amyloidinduced Toxicity Models.

Aim: The aim of this study is to examine the effect of etifoxine on β-amyloid-induced toxicity models.

Background: Etifoxine is an anxiolytic compound with a dual mechanism of action; it is a positive allosteric modulator of GABAergic receptors as well as a ligand for the 18 kDa mitochondrial Translocator Protein (TSPO). TSPO has recently raised interest in Alzheimer's Disease (AD), and experimental studies have shown that some TSPO ligands could induce neuroprotective effects in animal models.

Strain specific stress-modulating effects of candidate probiotics: A systematic screening in a mouse model of chronic restraint stress.

Background: Changes in the gut microbiota have been implicated in mood and cognition. In rodents, supplementation with certain bacteria have been shown to alleviate adverse effects of stress on gut microbiota composition and behaviour, but little is known of how the performance of different strains compare to each other. We took a systematic approach to test the efficacy of twelve candidate probiotic strains from ten species/sub-species of Bifidobacterium and Lactobacillus on behaviours and neuroendocrine responses of chronically stressed mice.

N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model.

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL.

Neuroprotective effect of a new photobiomodulation technique against Aβ peptide-induced toxicity in mice: Novel hypothesis for therapeutic approach of Alzheimer's disease suggested.

Introduction: Photobiomodulation was assessed as a novel treatment of Alzheimer's disease (AD) by the use of a new device RGn500 combining photonic and magnetic emissions in a mouse model of AD.

Methods: Following the injection of amyloid β 25-35 peptide in male Swiss mice, RGn500 was applied once a day for 7 days either on the top of the head or the center of abdomen or both.

Results: RGn500 daily application for 10 min produced a neuroprotective effect on the neurotoxic effects of amyloid β 25-35 peptide injection when this type of photobiomodulation was applied both on the head and on the abdomen.

In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm.

Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-β (Aβ) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs.

The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice.

Background And Purpose: Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.

Brain toxicity and inflammation induced in vivo in mice by the amyloid-β forty-two inducer aftin-4, a roscovitine derivative.

Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection.

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ₂₅₋₃₅ peptide-induced toxicity in vitro and in vivo in mice.

Rationale: Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents.

Increased amyloid-β peptide-induced memory deficits in phospholipid transfer protein (PLTP) gene knockout mice.

Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-β 25-35 (Aβ 25-35) peptide, a non-transgenic model of AD.

The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1-42 seeding and short-term memory deficits in the Aβ25-35 mouse model of Alzheimer's disease.

Alzheimer's disease pathomimetic toxicity could be induced in mice within one week after the intracerebroventricular (i.c.v.

Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid β fragment in rats.

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats.

Pharmacological interaction with the sigma1 (σ1)-receptor in the acute behavioral effects of antidepressants.

Selective agonists of the sigma-1 (σ(1)) ligand-operated chaperone protein, like igmesine or PRE-084, are antidepressants in preclinical depression models. σ(1)-Protein activation may contribute to the antidepressant efficacy of drugs known to act as selective serotonin-reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors through direct or indirect involvement of the σ(1)-receptor in the drug effect. We here compared antidepressant effects in two behavioral procedures, the forced swimming test (FST) and conditioned fear stress (CFS).

Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB.

The expression of Bcl-2, the major antiapoptotic member of the Bcl-2 family, is under complex controls of several factors, including reactive oxygen species (ROS). The sigma-1 receptor (Sig-1R), which was recently identified as a novel molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane (MAM), has been shown to exert robust cellular protective actions. However, mechanisms underlying the antiapoptotic action of the Sig-1R remain to be clarified.

Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation.

Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N-acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits.

Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice.

Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented.

Neurodevelopmental damage after prenatal infection: role of oxidative stress in the fetal brain.

Prenatal infection is a major risk responsible for the occurrence of psychiatric conditions in infants. Mimicking maternal infection by exposing pregnant rodents to bacterial endotoxin lipopolysaccharide (LPS) also leads to major brain disorders in the offspring. The mechanisms of LPS action remain, however, unknown.

Nitric oxide and oxidative stress in the brain of rats exposed in utero to cocaine.

The role of nitric oxide (NO) and lipid peroxidation (LPO) processes in the physiological deficits induced by in utero cocaine exposure was examined in rats. NO generation in the hippocampus and cortex was detected using the electron paramagnetic resonance and LPO products were measured as thiobarbituric acid reactive species (TBARS). Pregnant Sprague-Dawley rats received a daily intraperitoneal injection of 20 mg/kg cocaine (IUC) or saline solution for control dams (IUV) between E17-E20.

Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas.

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses.

Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil.

In the present study, we examined the interaction of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-inden-1-one hydrochloride (donepezil), a potent cholinesterase inhibitor, with two additional therapeutically relevant targets, N-methyl-d-aspartate (NMDA) and sigma(1) receptors. Donepezil blocked the responses of recombinant NMDA receptors expressed in Xenopus oocytes. The blockade was voltage-dependent, suggesting a channel blocker mechanism of action, and was not competitive at either the l-glutamate or glycine binding sites.