Abstract
BackgroundValproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24 hour-scale.MethodsThe 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).ResultsThe 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 % (Ø = 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).ConclusionsWith 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.
Highlights
Valproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures
The master mammalian biological clock is located in the hypothalamic suprachiasmatic nuclei (SCN) which imposes its temporal structure on the organism via neural and endocrine outputs [1,2]
The animals were randomly divided into various groups of mice each at 6 circadian stages denoted as 1, 5, 9, 13, 17, and Hours After Light Onset (HALO)
Summary
Valproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24 hour-scale. The master mammalian biological clock is located in the hypothalamic suprachiasmatic nuclei (SCN) which imposes its temporal structure on the organism via neural and endocrine outputs [1,2]. The SCN harbors the master circadian clock that coordinates most aspects of behavior and physiology [3,4]. This endogenous clock is responsible for biological rhythms which are influenced by synchronizing factors such as light, temperature and food intake [5]. Biological responses to various drugs follow circadian rhythms in experimental animals as well as human beings. Many drugs vary in potency and / or toxicity
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