Inhibition of nuclear factor kappaB is associated with neuroprotective effects of glycyrrhizic acid on glutamate-induced excitotoxicity in primary neurons.
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 kappaB (NF-kappaB) to its target elements. Western blot analysis of NF-kappaB inhibitor (IkappaBalpha) protein revealed that the inhibitory effect of glycyrrhizic acid on glutamate-induced activation of NF-kappaB activity was attributable to the inhibition of IkappaB 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-kappaB 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.
Cherng
Jaw-Ming
JM
Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, ROC.
Lin
Hsiang-Ju
HJ
Hung
Man-Shan
MS
Lin
Yi-Ruu
YR
Chan
Ming-Huan
MH
Lin
Jung-Chung
JC
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
D016328:NF-kappa B; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D013779:Tetrodotoxin; D019695:Glycyrrhizic Acid; D015763:2-Amino-5-phosphonovalerate; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D002118:Calcium