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.

Abstract

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.

• Authors: Izaskun Buendia, Javier Egea, Esther Parada, Elisa Navarro, Rafael León, María Isabel Rodríguez-Franco, Manuela G López
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 2 Pg. 288-96 (Feb 18 2015) ISSN: 1948-7193 [Electronic] United States
• PMID: 25393881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• MAPT protein, human
• Methylamines
• Neuroprotective Agents
• Protein Aggregates
• Receptors, Melatonin
• Receptors, Nicotinic
• tau Proteins
• Okadaic Acid
• HMOX1 protein, human
• Heme Oxygenase-1
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Melatonin

Topics

• Alzheimer Disease (drug therapy, enzymology, pathology)
• Amyloid beta-Peptides (toxicity)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Cholinesterase Inhibitors (pharmacology)
• Cytoskeleton (drug effects, metabolism, pathology)
• Heme Oxygenase-1 (metabolism)
• Humans
• MAP Kinase Signaling System (drug effects, physiology)
• Melatonin (pharmacology)
• Methylamines (pharmacology)
• Neuroprotective Agents (pharmacology)
• Okadaic Acid (toxicity)
• Phosphorylation (drug effects)
• Protein Aggregates (drug effects, physiology)
• Protein Kinase C (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Melatonin (metabolism)
• Receptors, Nicotinic (metabolism)
• tau Proteins (metabolism)