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

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.

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