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An optically active isochroman-2H-chromene conjugate potently suppresses neuronal oxidative injuries associated with the PI3K/Akt and MAPK signaling pathways

Authors: Ling-xue Tao1, Sha-sha Ji1, Dóra Szalóki2, Tibor Kovács2, Attila Mándi2, Sándor Antus2, Xun Ding1, Tibor Kurtán2, Hai-yan Zhang1
1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 400, H-4002 Debrecen, Hungary
Correspondence to: Tibor Kurtán: kurtan.tibor@science.unideb.hu, Hai-yan Zhang: hzhang@simm.ac.cn,
DOI: 10.1038/s41401-020-0391-9
Received: 26 August 2019
Accepted: 23 February 2020
Advance online: 11 May 2020

Abstract

Increasing evidence suggests that the use of potent neuroprotective agents featured with novel pharmacological mechanism would offer a promising strategy to delay or prevent the progression of neurodegeneration. Here, we provide the first demonstration that the chiral nonracemic isochroman-2H-chromene conjugate JE-133, a novel synthetic 1,3-disubstituted isochroman derivative, possesses superior neuroprotective effect against oxidative injuries. Pretreatment with JE-133 (1–10 μM) concentration-dependently prevented H2O2-induced cell death in SH-SY5Y neuroblastoma cells and rat primary cortical neurons. Pretreatment with JE-133 significantly alleviated H2O2-induced apoptotic changes. These protective effects could not be simply attributed to the direct free radical scavenging as JE-133 had moderate activity in reducing DPPH free radical. Further study revealed that pretreatment with JE-133 (10 μM) significantly decreased the phosphorylation of MAPK pathway proteins, especially ERK and P38, in the neuronal cells. In addition, blocking PI3K/Akt pathway using LY294002 partially counteracted the cell viability-enhancing effect of JE-133. We conclude that JE-133 exerts neuroprotection associated with dual regulative mechanisms and consequently activating cell survival and inhibiting apoptotic changes, which may provide important clues for the development of effective neuroprotective drug lead/ candidate.
Keywords: neurodegeneration; oxidative stress; apoptosis; MAPK pathway; PI3K/Akt pathway; SH-SY5Y neuroblastoma cells

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