Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative dis...Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative diseases are currently the leading cause of death and disability worldwide.In clinical use and neuroscience research,a solution for an effective diagnosis is in progress,but a prophylactic treatment to counteract this long-lasting plague for humanity is still unidentified.展开更多
Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is ...Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.展开更多
The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to for...The aggregation of Amyloid-β(Aβ)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 Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.展开更多
文摘Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative diseases are currently the leading cause of death and disability worldwide.In clinical use and neuroscience research,a solution for an effective diagnosis is in progress,but a prophylactic treatment to counteract this long-lasting plague for humanity is still unidentified.
文摘Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.
基金supported by a PHC Carlos J.Finlay program from Campus France(project 47069SA)to TM and CRT.The authors thank Drs Tsung-Ping Su and Yukio Kimura(NIDA,NIH,Baltimore,MD,USA)for the gift of GFP-tagged l proteinoverexpressing CHO cells,and the CECEMA animal facility of the University of Montpellier and the ZebraSens behavioral phenotyping platform for zebrafish models at MMDN.
文摘The aggregation of Amyloid-β(Aβ)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 Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.