Curcumin affords protection against valproic acid induced teratogenicity by curtailing oxidative stress and inhibiting CYP2C9 activity

Abstract

Administration of drugs during pregnancy is always done with immense caution, however multiple neurological ailments including epilepsy and depression warrant medical treatments even during pregnancy. This exposes the unborn fetus to killer teratogenic effects, thus warranting intense studies towards finding potential anti-teratogenic agents. We employed a valproic acid (VPA) induced model of fetotoxicity and teratogenicity in rats towards assessing the antiteratogenic activity of curcumin, an antioxidant well known for attenuating oxidative stress by increasing the content of glutathione and reducing the level of lipid hydroperoxide. We studied the level of GSH, catalase, SOD, ROS, TBARS and the activities of CYP2C9 and determined that VPA at a dose of 300 mg kg À1 body wt significantly decreased the levels of GSH, SOD and catalase and increased the levels of ROS, TBARS, mRNA expression and the levels of the CYP2C9 enzyme which is involved in the formation of the toxic metabolite (E)-2,4-diene-VPA. Upon co-administration of curcumin (100 150 and 200 mg kg À1 body wt) along with VPA the levels of GSH, SOD and catalase exhibited a significant increase and ROS, TBARS, mRNA expression and the level of CYP2C9 enzyme were found to be significantly decreased with respect to VPA. We conclude that the toxic metabolite (E)-2,4-diene-VPA is involved in the generation of oxidative stress subsequently contributing in the induction of malformations and anomalies and that curcumin affords dose dependent amelioration of the anomalies exerted by VPA. Our studies are suggestive of the fact that curcumin has antioxidant activity and can curtail the formation of toxic (E)-2,4-diene-VPA by inhibiting the CYP2C9 enzyme and finally protecting fetuses in a dose dependent manner.

Possible potentials of curcumin for pregnancies complicated by intra-uterine growth restriction: role of inflammation, angiogenesis, and oxidative stress

“…Moreover, they have shown that curcumin could significantly decrease mentioned fetal anomalies as well as a causing a significant increase in live births, body weight, crown to rump length in valproic acid-treated pregnant animals. The mentioned protective effects are believed to be achieved through decreasing CYP2C9 expression, ROS, and thiobarbituric acid reactive substances (TBARS) as well as a significant increase in superoxide dismutase (SOD), reduced glutathione (GSH), and CAT [ 61 ].…”

Curcumin bioavailability issues and its effect on birth defects

“…valproic acid etc) produces toxic ROS by impairing glutathione homeostasis and induced birth defects. 5,7 During gestation maternal circulation is directly linked to fetal circulation and the liver is the main site of drug metabolism hence, oxidative stress in the maternal system may induce oxidative stress in the foetuses which may cause fetotoxicity or embryotoxicity expressed in various ways including birth defects. 8 Some investigators also suggest that, increased oxidative stress to the developing foetus imposed by the intermediate metabolites of drugs (AEDs) may be responsible for the teratogenic effects.…”

“…3,4 It has been reported by several workers, being an effective antioxidant, curcumin counteracts oxidative stress-induced damages by retrieving the situation of redox disequilibration and thus recovering the activity of endogenous antioxidative defense system. [5][6][7] Since more than 50% of pregnancies are unplanned, sometimes the situation becomes crucial when a woman comes to know that she has to undergo treatment with some medication like epileptic drugs (might be a teratogenic) while she is pregnant and she is neither allowed undergoing for 'Medical Termination of Pregnancy (MTP) nor keep the treatment pending until delivery.…”

“…So, the products (natural or synthetic) which may have potential for helping to prevent birth defects among babies likely to be born from women taking any teratogenic drugs and also to allow the woman to continue with her unplanned pregnancy. 5…”

Anti-teratogenic potential and curtailing toxicity of valproic acid

“…However, curcumin affords dose dependent amelioration of the anomalies in fetus exerted by VPA. 56 A number of plant products have been reported to have excellent source of antioxidant with no side effects, in most of the published articles. Folic acid, vitamins and various plant products in various form now used as protective, prophylactic or ameliorative form.…”