Chronotolerance study of the antiepileptic drug valproic acid in mice

The influence of dosing-time on tolerance to VPA was investigated in 120 male Swiss mice synchronized under a light-dark cycle (12:12). The mean VPA lethal dose was first determined to be 850？±？0.2？mg/kg, i.p.. Such a dose was administered by i.p. route to a total of 90 mice divided in six circadian stages [1, 5, 9, 13, 17 and 21 Hours After Light Onset (HALO)] (15 mice/circadian time); 30 mice were used as control (5 mice / circadian time).The surviving treated mice exhibited a significant circadian variation in rectal temperature and body weight loss (p？<？0.001). The least rectal temperature change and body weight loss occurred when VPA was injected at 9 HALO. Drug dosing at 9 HALO resulted in -9？% weight loss whereas drug dosing at 17 HALO was -15？% (？？=？20.3 HALO？±？1.1？h, p？≤？0.0001). Lethal toxicity also varied according to circadian dosing-time (χ2？=？42.1, p？<？0.0001). The highest (60？%) and the lowest (6.67？%) survival rates were observed at 9 HALO and 17 HALO respectively. Cosinor analyses validated a significant circadian rhythm in survival duration with an acrophase at 8.4 HALO？±？0.75？h (p？<？0.001).With regards to these data the optimal tolerance to VPA occurred when the drug was administered in the second half of the light-rest span of mice which is physiologically analogous to the second half of the night for human patients.