Circadian time-dependent hepatic and renal toxicities to valproic acid in mice

• Published in: Biological rhythm research Vol. 46; no. 6; pp. 847 - 861
• Main Authors: Ben-Cherif, Wafa, Dridi, Ichrak, Haouas, Zohra, Miled, Abdelhedi, Aouam, Karim, Ben-Attia, Mossadok, Reinberg, Alain, Boughattas, Naceur A
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 02-11-2015
• Subjects: alanine transaminase; alkaline phosphatase; biological rhythms; circadian rhythm; Cosinor method; creatinine; hepatic toxicity; histopathology; liver; mice; nephrotoxicity; parenchyma (animal tissue); proximal tubules; renal toxicity; valproic acid
• ISSN: 1744-4179; 0929-1016; 1744-4179
• DOI: 10.1080/09291016.2015.1056437

This study aims to investigate whether hepatic and renal valproic acid (VPA) toxicities varied according to the dosing time in the 24-h scale in mice. VPA was administered by i.p. route to different groups of animals at four different circadian stages (1, 7, 13, and 19 h after light onset (HALO)). Biochemical study and histopathological examinations on liver and kidney sections were performed. The results showed that the hepatic and renal toxicity induced by VPA was time related. Animals treated at 19 HALO showed vacuolar degenerative changes, congestions, and inflammatory areas on liver parenchyma. Lesions within proximal tubules were observed in the kidney in groups treated at 19 HALO. The largest increases in alanine aminotransferase, alkaline phosphatase and plasma creatinine activities were also observed at 19 HALO. The obtained data indicate that the optimal hepatic and renal tolerance is observed when VPA was injected in the middle of the light-rest span of mice.