Effects of the antiepileptic drug valproic acid on the development of the axolotl (Ambystoma mexicanum): histological investigations.
In the amphibian Ambystoma mexicanum, valproic acid (VPA) causes retarded development and malformations including neural tube defects. Some of the observed abnormalities resemble exencephaly. We present the light microscopic characteristics of VPA-induced effects on the developing central nervous system (CNS) as well as on other developing tissues of this species. To induce malformations, various concentrations of VPA were applied to embryos from blastula stage on, either as 24-h pulse or as continuous exposure. In treated embryos the abnormal development of the CNS was indicated by retarded neurulation and disturbed closure of the neural folds. Furthermore, the neural epithelium was disorganized and its cells were less elongated than normal. Two ventricle lumina of various shapes arose in the neural tube and the neural epithelium extended laterally, whereas in the control animals the neural tube was small and overlaid the notochord only. In treated embryos intercellular spaces in neural epithelium as well as in connective tissue were enlarged and cell adhesion seemed disturbed in both tissues. The notochord underlying the neural plate appeared to be normally organized but oversized somites appeared, which periodically filled the space between notochord and notoplate. VPA also affected neural crest cells. Additional effects occurring were edema and liver damage. A high concentration of VPA even stopped development in early gastrulation. Characteristics of induced effects indicate an interaction between the drug and components of the extracellular matrix and the cytoskeleton.
Krätke
R
R
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Kirschbaum
F
F
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology; D000557:Ambystoma / Q000196:embryology; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002490:Central Nervous System / Q000002:abnormalities / Q000187:drug effects* / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D013723:Teratogens; D014635:Valproic Acid