Recently, loss of endogenous
glutathione during
N-methyl-D-aspartate (
NMDA) receptor-mediated excitotoxic injury, and the resultant overproduction of
reactive oxygen species (ROS) through an
arachidonic acid cascade process in brain, have been implicated in neuronal damage in various
neurodegenerative diseases.
Glutathione depletion induced by L-
buthionine-(S,R)-sulfoximine (BSO), an inhibitor of
glutathione synthesis, is known to cause
arachidonic acid-mediated excitotoxicity in primary mixed cortical cultures. The aim of this study was to investigate whether
esculetin (6,7-dihydroxycoumarin), an inhibitor of
lipoxygenase, protects against neurotoxicity induced by
NMDA or BSO. We observed that neurotoxicity induced by
NMDA but not
kainic acid was attenuated by
esculetin. At the same concentration (100 µM),
esculetin attenuated the (45)Ca(2+) uptake elevation induced by
NMDA.
Free radical-mediated neuronal injury induced by H(2)O(2) and
xanthine/
xanthine oxidase was concentration-dependently blocked by
esculetin.
Esculetin (1-30 µM) dose-dependently inhibited BSO-induced neuronal injury. In addition, arachidonate-induced neurotoxicity was completely blocked by
esculetin. BSO also
reduced glutathione peroxidase (GPx) activity, but did not change
glutathione reductase (GR) activity 24 h
after treatment.
Esculetin dose-dependently increased GR activity, but did not alter GPx activity. These findings suggest that
esculetin can contribute to the rescue of neuronal cells from
NMDA neurotoxicity and that this protective effect occurs partly through
NMDA receptor modulation and the sparing of
glutathione depletion.