Valproic Acid Increases Formation of Reactive Oxygen Species and Induces Apoptosis in Postimplantation Embryos: A Role for Oxidative Stress in Valproic Acid-Induced Neural Tube Defects

Abstract

Exposure to the anticonvulsant valproic acid (VPA) during the first trimester of pregnancy is associated with an increased risk of congenital malformations including heart defects, craniofacial abnormalities, skeletal and limb defects, and, most frequently, neural tube defects (NTDs). The mechanisms by which VPA induces teratogenic effects are not fully understood, although previous studies support a role for oxidative stress. To investigate the effects of VPA on early development, a wholeembryo culture model was used to evaluate the protective effects of antioxidants, measure intracellular reactive oxygen species (ROS) levels, and assess markers of oxidative damage and apoptosis. Furthermore, in vivo teratological evaluations of antioxidant protection were also completed. VPA (0.60 mM in embryo culture, 400 mg/kg in vivo) induced significant decreases in embryonic growth and increases in NTDs. Of the antioxidants tested, catalase provided partial protection against VPA-mediated reductions in morphological and developmental growth parameters in both whole-embryo culture and in vivo systems. VPA exposure resulted in an increase in ROS staining in the head region, as assessed by whole-mount staining with 5-(and-6)-chloromethyl-2Ј,7Ј-dichlorodihydrofluorescein diacetate. Markers of embryonic oxidative damage including 8-hydroxyguanosine, 4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA treatment. Increased ROS levels were correlated with increased staining for apoptotic markers, as assessed by Western blotting and immunohistochemistry. Addition of catalase to the medium attenuated VPA-induced increases in ROS formation and apoptosis. These studies identify regions of the embryo susceptible to ROS and apoptosis induced by VPA, thus establishing a possible molecular pathway by which VPA exerts teratogenicity.

Investigation of the Effects of Edaravone on Valproic Acid Induced Tissue Damage in Pancreas

“…In previous studies, it was reported that antiepileptic drugs, especially VPA, trigger tissue injury and increase the production of reactive oxygen species by several mechanism and have diverse effects on defence system (20,21). There are many studies that show the elevation of LPO levels in blood and tissues under VPA treatment (20,22,23).…”

Valproic Acid Increases Formation of ROS and Interferes with Hearing Recovery after Noise Trauma in Guinea Pigs

“…VPA-induced hepatotoxicity and neural tube defects have been reported, and the most likely mechanism is associated with oxidative stress [3,4] .…”

“…High-level noise leads to significantly decreased blood flow to the stria vascularis [13] ; then, resolution of the ischemic event by reperfusion leads to an elevation in ROS in the inner ear, which could elevate the levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and glutathione reductase) in cochlear tissue [14][15][16][17][18] . Also, oxidative stress has been associated with VPA toxicity [3,4] . Thus, we were interested in the effects of VPA on NIHL.…”

“…Even though some cases of ototoxicity using this drug have been reported [1,2] , the mechanism of the ototoxicity remains elusive. Several studies have proposed the mechanism that VPA toxicity is associated with oxidative stress [3,4] . Also, the generation of oxygen free radicals in the cochlea after noise exposure is a potential mechanism of noise-induced hearing loss (NIHL).…”

Evaluation of Oxidative DNA Damage and Its Relation with Anthropometric Indices in Healthy Adolescents

“…Oxidative stress (OS) is occurred when production process of ROS is accelerated or when the mechanisms involved in keeping cell environment are disordered [1,2]. OS is more likely along with pathological phenomena such as aging, arteriosclerosis, high blood pressure, renal disorders, changes in the immune system, damage to revascularization cycle, nerve damage, cancers and destruction and inflammation conditions [3,4,5,6]. OS can simultaneously result damage in biomolecules including lipids, proteins, nucleic acids and carbohydrates [7,8].…”