Chronotoxicity of sodium valproate and its mechanisms in mice: Dose-concentration-response relationship

Shigehiro Ohdo, Shigeyuki Nakano, Nobuya Ogawa

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Abstract

A significant circadian rhythm of acute toxicity was demonstrated in mice with intraperitoneal (i.p.) injection of sodium valproate (VPA). The role of pharmacokinetics on the rhythms of the toxicity and electroshock seizure (ES) threshold was investigated. ICR male mice, housed under a light-dark (12 :12) cycle, were injected intraperitoneally 1200 mg/kg for the acute toxicity study and 300 mg/kg for the anticonvulsant effect study. In the acute toxicity, the highest mortality was found when VPA was injected at 1700 and the lowest at 0900 or 0100. The time course of mean plasma and brain VPA concentrations after an injection of VPA was not different between mice injected at 1700 and mice injected at 0100. In the anticonvulsant effect, no significant circadian rhythm was demonstrated for both the ES threshold and the plasma VPA concentrations after i.p. Injection, although a significant rhythm has been reported for them after oral administration. The results suggest that the circadian rhythm in the mortality after an i.p. Injection of VPA may be due to the rhythm in the sensitivity of the central nervous system to the drug and that the mechanism underlying the rhythm of VPA acute toxicity is different from that of the anticonvulsant action of VPA. The route and the time of drug administration are essentially important to study the anticonvulsant effect and acute toxicity of VPA in mice.

Original languageEnglish
Pages (from-to)229-235
Number of pages7
JournalChronobiology International
Volume6
Issue number3
DOIs
Publication statusPublished - Jan 1 1989

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Valproic Acid
Anticonvulsants
Circadian Rhythm
Intraperitoneal Injections
Electroshock
Seizures
Drug Administration Routes
Central Nervous System Agents
Inbred ICR Mouse
Mortality
Oral Administration
Pharmacokinetics
Light
Injections
Brain

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Chronotoxicity of sodium valproate and its mechanisms in mice : Dose-concentration-response relationship. / Ohdo, Shigehiro; Nakano, Shigeyuki; Ogawa, Nobuya.

In: Chronobiology International, Vol. 6, No. 3, 01.01.1989, p. 229-235.

Research output: Contribution to journalArticle

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