Effects of chronic treatment with valproate and oxcarbazepine on testicular development in rats

Seizure. 2011 Apr;20(3):203-7. doi: 10.1016/j.seizure.2010.11.019. Epub 2010 Dec 18.


Purpose: The aim of this study was to examine the potential effects of valproate (VPA) and oxcarbazepine (OXC) on testicular development in rats.

Methods: Forty-two Wistar rats were randomly divided into three groups of 14 rats each. Each group received the following via gavage over 90 days: group 1, tap water (control group); group 2, VPA (300mg/kg/day); group 3, OXC (100mg/kg/day). After sacrifice, body, testicular and epididymidis weights were measured. Testes were sampled, fixed and processed, and quantitative morphometric analysis of Sertoli cells, spermatocytes and spermatids was performed in stages II, V and XII by histopathological examination. Immunohistochemical staining was performed to transform growth factor beta 1 (TGF-β1) and p53, and the apoptotic index was assessed using the TUNEL method.

Results: Testis and relative testis weights were significantly lower in the VPA group compared to the control group (p<0.05). Spermatogonia, pachytene spermatocyte and round spermatocyte numbers decreased in all stages in both the VPA and OXC groups compared to the control group, though this was not statistically significant (p>0.05). Apoptotic cell counts and p53 immunoreaction were significantly high and TGF-β1 expression was significantly lower in the VPA group compared to that of the control group (p<0.05). In the OXC group, p53 immunoreaction and TGF-β1 expression decreased compared to the control group, but this difference did not attain statistical significance (p>0.05).

Conclusions: Our results show that VPA treatment from prepuberty to adulthood significantly negatively affects spermatogenesis, not only by reducing testicular weight, but also by increasing apoptotic death and p53 and decreasing TGF-β1 activation. OXC has a minimal side effect on testicular development.

MeSH terms

  • Animals
  • Animals, Newborn
  • Anticonvulsants / blood
  • Anticonvulsants / pharmacology*
  • Body Weight / drug effects
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood
  • Carbamazepine / pharmacology
  • Dose-Response Relationship, Drug
  • In Situ Nick-End Labeling / methods
  • Male
  • Organ Size / drug effects
  • Oxcarbazepine
  • Rats
  • Rats, Wistar
  • Sertoli Cells / drug effects
  • Spermatids / drug effects
  • Spermatocytes / drug effects
  • Testis / cytology
  • Testis / drug effects*
  • Testis / growth & development*
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Valproic Acid / blood
  • Valproic Acid / pharmacology*


  • Anticonvulsants
  • Transforming Growth Factor beta1
  • Tumor Suppressor Protein p53
  • Carbamazepine
  • Valproic Acid
  • Oxcarbazepine