Dual Effect of Saikogenin D: In vitro Inhibition of Prostaglandin E₂ Production and Elevation of Intracellular Free Ca²⁺ Concentration in C6 Rat Glioma Cells

Abstract

To clarify the pharmacological profile of saikogenin D, we examined the effect of saikogenin D on prostaglandin E₂ (PGE₂) production and intracellular free Ca²⁺ concentration ([Ca²⁺]_i) in C6 rat glioma cells. Saikogenin D (1 - 20 μM) inhibited PGE₂ production induced by the Ca²⁺ ionophore A23187 in a concentration-dependent manner with the IC₅₀ of about 3 μM. Saikogenin D did not affect the conversion of arachidonic acid into PGE₂ in microsomal preparations. On the other hand, saikogenin D elevated [Ca²⁺]_i in a concentration-dependent manner (10 - 100 μM) with the EC₅₀ value of about 35 μM in the presence or absence of extracellular Ca²⁺. These results suggest that saikogenin D possesses a dual effect: an inhibition of A23187-induced PGE₂ production without a direct inhibition of cyclooxygenase activity; and an elevation of [Ca²⁺]_i that is attributed to Ca²⁺ release from intracellular stores.

References

• 1 Bermejo Benito P, Abad Martinez M J, Silvan Sen A M, Sanz Gomez A, Fernandez Matellano L, Sanchez Contreras S. et al . In vivo and in vitro anti-inflammatory activity of saikosaponins.  Life Sci. 1998;  63 1147-56
• 2 Nishioka Y, Kyotani S, Miyamura M, Kusunose M. Influence of time of administration of a Shosaiko-to extract granule on blood concentration of its active constituents.  Chem Pharm Bull (Tokyo). 1992;  40 1335-7
• 3 Dayton E T, Majo E O. Recombinant human interleukin 1 induces production of prostaglandins in primary human fetal astrocytes and immortalized human fetal astrocyte cultures.  J Neuroimmunol. 1996;  71 11-8
• 4 Almer G, Teismann P, Stevie Z, Halaschek-Wiener J, Deecke L, Kostic V. et al . Increased levels of the pro-inflammatory prostaglandin PGE₂ in CSF from ALS patients.  Neurology. 2002;  58 1277-9
• 5 Stephenson D T, Lemere C A, Selkoe D J, Clemens J A. Cytosolic phospholipase A₂ (cPLA₂) immunoreactivity is elevated in Alzheimer's disease brain.  Neurobiol Dis. 1996;  3 51-63
• 6 Weaver J A, Maddox J F, Cao Y Z, Mullarky I K, Sordillo L M. Increased 15-HPETE production decreases prostacyclin synthase activity during oxidant stress in aortic endothelial cells.  Free Rad Biol Med. 2001;  30 299-308
• 7 Matsushima T. Drug-induced pneumonitis and related diseases.  Nippon Naika Gakkai Zasshi. 1997;  86 457-62
• 8 Nakatani K, Nakahata N, Arakawa T, Yasuda H, Ohizumi Y. Inhibition of cyclooxygenase and prostaglandin E₂ synthesis by γ-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells.  Biochem Pharmacol. 2002;  63 73-9
• 9 Tsukii K, Nakahata N, Watanabe K, Tsurufuji S, Ohizumi Y. Comparison of tBuBHQ with chemotactic peptide and phorbol ester in O₂ ^- production in HL-60 cells.  Eur J Pharmacol. 1996;  298 87-95
• 10 Nakahata N, Ishimoto H, Mizuno K, Ohizumi Y, Nakanishi H. Dual effects of mastoparan on intracellular free Ca²⁺ concentrations in human astrocytoma cells.  Br J. Pharmacol 1994;  112 299-303