The present study evaluated antioxidant and neuroprotective activities of 
hesperidin, a flavanone mainly isolated from citrus fruits, and its aglycone 
hesperetin using cell-free bioassay system and primary cultured rat cortical 
cells. Both hesperidin and hesperetin exhibited similar patterns of 
1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. While hesperidin 
was inactive, hesperetin was found to be a potent antioxidant, inhibiting lipid 
peroxidation initiated in rat brain homogenates by Fe2+ and L-ascorbic acid. In 
consistence with these findings, hesperetin protected primary cultured cortical 
cells against the oxidative neuronal damage induced by H2O2 or xanthine and 
xanthine oxidase. In addition, it was shown to attenuate the excitotoxic 
neuronal damage induced by excess glutamate in the cortical cultures. When the 
excitotoxicity was induced by the glutamate receptor subtype-selective ligands, 
only the N-methyl-D-aspartic acid-induced toxicity was selectively and markedly 
inhibited by hesperetin. Furthermore, hesperetin protected cultured cells 
against the A(beta(25-35))-induced neuronal damage. Hesperidin, however, exerted 
minimal or no protective effects on the neuronal damage tested in this study. 
Taken together, these results demonstrate potent antioxidant and neuroprotective 
effects of hesperetin, implying its potential role in protecting neurons against 
various types of insults associated with many neurodegenerative diseases.