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.