Inhibition of nuclear factor κB is associated with neuroprotective effects of glycyrrhizic acid on glutamate-induced excitotoxicity in primary neurons

Abstract

Glycyrrhizic acid is an herbal drug with a broad spectrum of antiviral activities and pharmacological effects and multiple sites of action. We investigated whether glycyrrhizic acid protects against glutamate-induced excitotoxicity and the underlying mechanisms. We found that glycyrrhizic acid protected against neurotoxicity in rat primary neuronal cultures and hippocampal slices by suppression of the glutamate-induced apoptosis. Glycyrrhizic acid conferred neuroprotective properties in a concentration-dependent manner, as determined by cell survival, apoptosis, and Ca 2+ influx. Glycyrrhizic acid selectively inhibited the Ca 2+ influx activated through N-methyl- d-aspartate (NMDA) receptor by glutamate, but not through membrane depolarization elicited by high K + induction. Glycyrrhizic acid treatment also diminished glutamate-induced DNA fragmentation and cleavage of poly (ADP-ribose) polymerase (PARP). Electrophoretic mobility shift assay (EMSA) indicated that glycyrrhizic acid inhibited the binding activity of nuclear factor κB (NF- κB) to its target elements. Western blot analysis of NF- κB inhibitor (I κBα) protein revealed that the inhibitory effect of glycyrrhizic acid on glutamate-induced activation of NF- κB activity was attributable to the inhibition of I κB kinase activity. Thus, the site of action of glycyrrhizic acid could be a downstream consequence of Ca 2+entry through NMDA receptors and that NF- κB may be one downstream target in this process. These observations suggest that glycyrrhizic acid may be of therapeutic value for the prevention of cerebral damage elicited by the glutamate.