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

Ling xue Tao, Sha sha Ji, Dóra Szalóki, Tibor Kovács, Attila Mándi, S. Antus, Xun Ding, Tibor Kurtán, Hai yan Zhang

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
JournalActa Pharmacologica Sinica
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • MAPK pathway
  • PI3K/Akt pathway
  • SH-SY5Y neuroblastoma cells
  • apoptosis
  • neurodegeneration
  • oxidative stress

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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