The melatonin-N,N-dibenzyl(N-methyl)amine hybrid ITH91/IQM157 affords neuroprotection in an in vitro Alzheimer's model via hemo-oxygenase-1 induction.
We have investigated the protective effects of ITH91/IQM157, a hybrid of melatonin and N,N-dibenzyl(N-methyl)amine, in an in vitro model of Alzheimer's disease (AD)-like pathology that combines amyloid beta (Aβ) and tau hyperphosphorylation induced by okadaic acid (OA), in the human neuroblastoma cell line SH-SY5Y. Combination of subtoxic concentrations of Aβ and OA caused a significant toxicity of 40% cell death, which mainly was apoptotic; this effect was accompanied by retraction of the cells' prolongations and accumulation of thioflavin-S stained protein aggregates. In this toxicity model, ITH91/IQM157 (1-1000 nM) reduced cell death measured as MTT reduction; at 100 nM, it prevented apoptosis, retraction of prolongations, and Aβ aggregates. The protective actions of ITH91/IQM157 were blocked by mecamylamine, luzindol, chelerythrine, PD98059, LY294002, and SnPP. We show that the combination of melatonin with a fragment endowed with AChE inhibition in a unique chemical structure, ITH91/IQM157, can reduce neuronal cell death induced by Aβ and OA by a signaling pathway that implicates both nicotinic and melatonin receptors, PKC, Akt, ERK1/2, and induction of hemoxygenase-1.
Instituto Teófilo Hernando (ITH), Universidad Autónoma de Madrid , Madrid 28029, Spain.
Izaskun
I
Buendia
Javier
J
Egea
Esther
E
Parada
Elisa
E
Navarro
Rafael
R
León
María Isabel
MI
Rodríguez-Franco
Manuela G
MG
López
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008550:Melatonin / Q000494:pharmacology*; D008744:Methylamines / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044094:Receptors, Melatonin / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C054369:MAPT protein, human; D008744:Methylamines; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D044094:Receptors, Melatonin; D011978:Receptors, Nicotinic; D016875:tau Proteins; D019319:Okadaic Acid; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D008550:Melatonin
Alzheimer’s disease; ITH91/IQM157; SH-SY5Y; acetylcholinestaerase inhibitor; beta-amyloid; melatonin; neuroprotection; okadaic acid