  In the present study, we show that ascorbic acid dose-dependently inhibited
interleukin-1beta (IL-1beta)-mediated PGE2 synthesis in the human neuronal cell
line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid
augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic
acid had no synergistic effect along with other COX inhibitors (SC-58125 and
indomethacin). The inhibition of IL-1beta-mediated PGE2 synthesis by ascorbic
acid was not due to the inhibition of the expression of COX-2 or microsomal
prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently
(0.1-100 microM) produced a significant reduction in IL-1beta-mediated
production of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable
indicator of free radical formation, suggesting that the effects of ascorbic
acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance
of the neuronal redox status since COX activity is known to be enhanced by
oxidative stress. Our results provide in vitro evidence that the
neuroprotective effects of ascorbic acid may depend, at least in part, on its
ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its
antioxidant properties. Further, these experiments suggest that a combination
of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more
sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with
lower doses of aspirin, thereby avoiding the side effects of the usually high
dose aspirin treatment.
