Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in rats.
OBJECTIVE
We aimed to define the morphologic effects of valproate (VPA) and oxcarbazepine (OXC) on ovarian folliculogenesis in rats.


METHODS
Forty female wistar rats (21-24 days old and weighted between 46.4 and 55.3 g) were divided equally into 4 experimental groups, which were applied tap water (control group), 300 mg/kg/day VPA, 100 mg/kg/day OXC, and both VPA and OXC via gavage for 90 days. Ovaries of the rats on proestrous and diesterous phase of estrous cycle according to daily vaginal smear were taken out and placed in a fixation solution. Immunohistochemical and apoptosis (TUNEL) staining protocols were applied.


RESULTS
The number of follicles decreased and that of corpora lutea increased significantly in OXC, VPA, and OXC+VPA treated groups compared with control group (p < 0.05). The number of TUNEL positive ovarian follicles was 1.40 +/- 0.52 in control group, but it significantly increased to 3.50 +/- 0.53, 3.50 +/- 0.53, and 4.90 +/- 0.88 in VPA, OXC, and VPA+OXC groups (p < 0.0001). The increase in the number of TUNEL positive granulosa cells was also significant for OXC and VPA+OXC groups (p < 0.0001). Immunohistochemical HSCORE decreased for TGF beta 1 and IGF1 staining and increased for P53 staining in all drug groups compared with control group (p < 0.001). Intensity of P53 labeling increased, while intensity of TGF beta 1, IGF-1, and GDF-9 immunoreactivity decreased significantly in all drug groups compared with control group (p < 0.001).


CONCLUSIONS
Long-term treatment with VPA or OXC from prepuberty to adulthood causes apoptosis and deterioration of folliculogenesis in rat ovarian follicles.
Cansu
Ali
A
Department of Pediatric Neurology, Karadeniz Technical University, Faculty of Medicine, Merkez/Trabzon, Turkey. acansu2003@yahoo.com
Giray
Seren G
SG
Serdaroglu
Ayse
A
Erdogan
Deniz
D
Coskun
Zafer K
ZK
Korucuoglu
Umit
U
Biri
Aydan A
AA
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003338:Corpus Luteum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy*; D005260:Female; D007150:Immunohistochemistry; D008233:Lymphotoxin-alpha / Q000187:drug effects / Q000378:metabolism; D006080:Ovarian Follicle / Q000187:drug effects* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000078330:Oxcarbazepine; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D008233:Lymphotoxin-alpha; D002220:Carbamazepine; D014635:Valproic Acid; D000078330:Oxcarbazepine