Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets

Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets

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J Psychiatry Neurosci 2007;32(1):17-22

Tatsuyuki Akimoto, MD, PhD; Ichiro Kusumi, MD, PhD; Katsuji Suzuki, MD, PhD; Takuya Masui, MD; Tsukasa Koyama, MD, PhD

Akimoto, Kusumi, Suzuki, Masui, Koyama — Department of Psychiatry, Hokkaido University Graduate School of Medicine,Kita-ku, Supporo; Akimoto — Department of Psychiatry, Kushiro City General Hospital, Kushiro, Japan

Abstract

Objective: Valproate (VPA) is effectively used in the treatment of bipolar disorder, although the mechanism of action is unclear. In patients with bipolar disorder, 5-hydroxytryptamine (5-HT)–induced intraplatelet calcium (Ca) mobilization has been shown to be enhanced.
Methods: We examined the effect of VPA on 5-HT–induced Ca response in the platelets of normal subjects, in the presence of a calmodulin antagonist W-7 (N-[6-aminohexyl]-5-chloro-1-naphthalenesulfonamide), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or PKC inhibitors staurosporine and bisindolylmaleimide II.
Results: VPA inhibited the 5-HT–induced Ca response in a concentration-dependent manner. For calmodulin pathways, W-7 enhanced the 5-HT–stimulated Ca response, which was not affected by VPA. For PKC pathways, PMA reduced the Ca response, although both PKC inhibitors had no effect. PMA, staurosporine or bisindolylmaleimide II reversed the inhibitory effect of VPA on the Ca response, while W-7 did not modify it.
Conclusion: These findings suggest the possibility that the mechanism of action of VPA may be partly related to PKC signalling.

Résumé

Objectif : Le valproate (VPA) est efficace dans le traitement du trouble bipolaire, bien que son mécanisme d’action ne soit pas clair. Chez les patients atteints de trouble bipolaire, on a démontré que la mobilisation du calcium (Ca) intraplaquettaire catalysée par la 5-hydroxytryptamine (5-HT) s’est améliorée.
Méthodes : Nous avons étudié l’effet du VPA sur la réponse du Ca catalysée par la 5-HT dans les plaquettes de sujets normaux, en présence de W-7 (N-[6-aminohexyl]-5-chloro-1-naphthalenèsulfonamide), un antagoniste de la calmoduline, de phorbol 12-myristate 13-acétate (PMA), activateur de la protéine kinase C (PKC), ou de staurosporine et de bisindolylmaléimide II, inhibiteurs de la PKC.
Résultats : Le VPA a inhibé la réponse du Ca catalysée par la 5-HT d’une façon reliée à la concentration. Dans le cas des voies de la calmoduline, le W-7 a amélioré la réponse du Ca catalysée par la 5-HT, que le VPA n’a pas affectée. Dans le cas des voies de la PKC, le PMA a réduit la réponse du Ca, même si les deux inhibiteurs de la PKC n’ont eu aucun effet. Le PMA, la staurosporine ou le bisindolylmaléimide II ont inversé l’effet inhibiteur du VPA sur la réponse du Ca, tandis que le W-7 ne l’a pas modifiée.
Conclusion : Ces constatations indiquent que le mécanisme d’action du VPA pourrait être lié en partie aux signaux transmis par la PKC.


Competing interests: None declared.

Acknowledgements: This work was partly supported by grants-in-aid for Soul and diseases-of-the-nervous-system research (T. Koyama) from the Japanese Ministry of Health, Labor and Welfare, and for Scientific Research No. 17591192 (I. Kusumi) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Contributors: Drs. Kusumi, Koyama and Suzuki designed the study. Drs. Akimoto and Suzuki participated in the acquisition of data, which Drs. Akimoto, Kusumi and Masui analyzed. Drs. Akimoto and Kusumi wrote the article, and Drs. Kusumi, Masui, Koyama and Suzuki critically reviewed it. All authors gave approval for the final version of the article to be published.

Submitted Apr. 8, 2006; Revised Jun. 9, 2006; Aug. 15, 2006; Aug. 21, 2006; Accepted Aug. 21, 2006

Correspondence to: Dr. Ichiro Kusumi, Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15 — West 7, Kita-ku, Sapporo 060-8638, Japan; fax 81&plus11-706-5081; ikusumi@med.hokudai.ac.jp