Effects of Ginsenoside Rd and Decursinol on the Neurotoxic Responses Induced by Kainic Acid in Mice

Abstract

In the present study, we examined the effects of ginsenoside Rd (G-Rd) and decursinol (DC) on various neurotoxic responses induced by kainic acid (KA) administered intracerebroventricularly (i. c. v.) in ICR mice. Ginseng total saponin (GTS) inhibited the KA (0.5 μg)-induced lethal toxicity in a dose-dependent manner. Furthermore, G-Rd, a component of GTS, also attenuated the KA-induced lethal toxicity as well as DC pretreated orally for 30 min. In ICR mouse, neurotoxic damage induced by KA (0.1 μg) in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. G-Rd and DC did not affect the pyramidal cell death in CA3 hippocampal region. In an immunohistochemical study, KA dramatically increased phospho-ERK and decreased phospho-CREB in the hippocampal area. G-Rd and DC attenuated, in part, the increased phospho-ERK and the decreased phospho-CREB protein levels. However, DC potentiated the increased c-Fos and c-Jun protein levels in the hippocampus induced by KA. Thus, our results suggest that the phosphorylation of ERK or the dephosphorylation of CREB protein may play a major role in the regulation of lethal toxicity induced by KA, whereas cell death in the hippocampal CA3 region induced by KA administered i. c. v. may not be directly mediated by ERK phosphorylation and CREB phosphorylation in the mouse.

Abbreviations

KA:Kainic acid

G-Rd:Ginsenoside Rd

DC:Decursinol

i. c. v.:intracerebroventricular

CNS:Central nervous system

DG:dentate gyrus

MAPK:Mitogen-activated protein kinase

ERK:Extracellular signal-regulated protein kinase

CREB:cyclic AMP-response element binding protein

IR:Immunoreactivity

S.E.M.:Standard error of the means

Ginsenoside Rd - Panax ginseng C. A. Meyer - Araliaceae - decursinol - Angelica gigas Nakai - Umbelliferae - hippocampal cell death - kainic acid - lethality - ERK - CREB

References

• 1 Izquierdo L A, Barros D M, Ardenghi P G, Pereira P, Rodrigues C, Choi H, Medina J H, Izquierdo I. Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning.  Behav Brain Res. 2000;  111 93-8
• 2 Ben-Ari Y, Gho M. Long-lasting modification of the synaptic properties of rat CA3 hippocampal neurones induced by kainic acid.  J Physiol. 1988;  404 365-84
• 3 Sperk G, Lassmann H, Baran H, Kish S J, Seitelberger F, Hornykiewicz O. Kainic acid induced seizures: neurochemical and histopathological changes.  Neuroscience. 1983;  10 1301-15
• 4 Kim Y H, Choi S S, Lee J K, Won J S, Choi M R, Suh H W. Possible roles of JNK pathway in the regulation of hippocampal proenkephalin and immediate early gene expression induced by kainic acid.  Mol Cells. 2001;  11 144-50
• 5 Jeon S H, Kim Y S, Bae C D, Park J B. Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure.  Exp Mol Med. 2000;  32 227-30
• 6 Imaki J, Yoshida K, Yamashita K. A developmental study of cyclic AMP-response element binding protein (CREB) by in situ hybridization histochemistry and immunocytochemistry in the rat neocortex.  Brain Res. 1994;  651 269-74
• 7 Moore A N, Waxham M N, Dash P K. Neuronal activity increases the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in rat hippocampus and cortex.  J Biol Chem. 1996;  271 14 214-20
• 8 Won J S, Kim Y H, Song D K, Suh H W. The effect of cycloheximide on the regulation of proenkephalin and prodynorphin gene expressions induced by kainic acid in rat hippocampus.  Brain Res Mol Brain Res. 1997;  47 303-10
• 9 Kim H S, Jang C G, Oh K W, Oh S, Rheu H M, Rhee G S, Seong Y H, Park W K. Effects of ginseng total saponin on morphine-induced hyperactivity and conditioned place preference in mice.  J Ethnopharmacol. 1998;  60 33-42
• 10 Tsang D, Yeung H W, Tso W W, Peck H. Ginseng saponins: influence on neurotransmitter uptake in rat brain synaptosomes.  Planta Med. 1985;  51 221-4
• 11 Ahn K S, Sim W S, Kim I H. Decursin: a cytotoxic agent and protein kinase C activator from the root of Angelica gigas .  Planta Med. 1996;  62 7-9
• 12 Ahn K S, Sim W S, Lee I K, Seu Y B, Kim I H. Decursinol angelate: a cytotoxic and protein kinase C activating agent from the root of Angelica gigas .  Planta Med. 1997;  63 360-1
• 13 Ryu K S, Yook C S. Studies on the coumarins of the root of Angelica gigas Nakai.  Yakhak Hoeji. 1967;  11 22-6
• 14 Laursen S E, Belknap J K. Intracerebroventricular injections in mice. Some methodological refinements.  J Pharmacol Methods. 1986;  16 355-7
• 15 Baker H, Farbman A I. Olfactory afferent regulation of the dopamine phenotype in the fetal rat olfactory system.  Neuroscience. 1993;  52 115-34
• 16 Attele A S, Wu J A, Yuan C S. Ginseng pharmacology: multiple constituents and multiple actions.  Biochem Pharmacol. 1999;  58 1685-93
• 17 Wen T C, Yoshimura H, Matsuda S, Lim J H, Sakanaka M. Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute forebrain ischemia.  Acta Neuropathol. 1996;  91 15-22
• 18 Kim S E, Lee Y H, Park J H, Lee S K. Ginsenoside-Rs3, a new diol-type ginseng saponin, selectively elevates protein levels of p53 and p21WAF1 leading to induction of apoptosis in SK-HEP-1 cells.  Anticancer Res. 1999;  19 487-91
• 19 Kim Y S, Jin S H, Lee Y H, Kim S I, Park J D. Ginsenoside Rh2 induces apoptosis independently of Bcl-2, Bcl-xL, or Bax in C6Bu-1 cells.  Arch Pharm Res. 1999;  22 448-53
• 20 Zhang X, Le Gal La Salle G, Ridoux V, Yu P H, Ju G. Prevention of kainic acid-induced limbic seizures and Fos expression by the GABA-A receptor agonist muscimol.  Eur J Neurosci. 1997;  9 29-40