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.