Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: Evaluation of the teratogenic effects of its amide derivatives in NMRI mice

Abstract

The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates.

Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice

“…To compare the potencies of the acylurea derivatives with that of VPA with regard to induction of axial skeleton malformations, the bone and cartilage of the fetuses treated with either vehicle, VPA, or an analogue were double-stained, and the vertebrae and ribs were examined (Table 4). Our findings were similar to those noted in previous reports (Menegola et al, 1998;Okada et al, 2004Okada et al, , 2008, with VPA at 1.8 mmol/kg inducing a significant increase in the incidence rates of a number of skeletal malformations, including fusion and transformation of the vertebrae, fusion of the ribs, development of supernumerary ribs (SNRs), and an extra (eighth) pair of vertebrosternal ribs. Ribs were partially or completely fused at the bone and cartilage levels, and an increased incidence of full SNRs at the thoracolumbar border was also noted.…”

“…In the present study, VPA induced exencephaly in fetuses at a rate of 18.7% when administered at 3.6 mmol/kg as previous studies (Okada et al, 2004(Okada et al, , 2008. In contrast, no fetal NTDs were induced in NMRI mice dosed with EHU, EMPU, or MBU at up to 4.8 mmol/kg.…”

“…VPA is known to induce high embryo lethality, growth retardation, and NTD in fetuses on Cesarean section at GD 18 (Nau, 1986;Okada et al, 2004Okada et al, , 2008. In this study, treatment with VPA at 3.6 mmol/kg induced an increase in the rate of fetal loss (20%) and a decrease in fetal weight (neither statistically significant) compared with values observed in the control group (Table 3).…”

“…No effects on these parameters were noted on administration of VPA at 1.8 mmol/kg. With regard to external malformations, VPA disrupted neural tube closure in NMRI embryos as previously reported (Nau, 1986;Okada et al, 2004Okada et al, , 2008, inducing NTDs in fetuses at a rate of 1.7% with 1.8 mmol/kg and 18.7% with 3.6 mmol/kg. These VPAinduced NTDs were classified as exencephaly with or without a cleft face as a result of anterior neural tube closure failure.…”

“…Pregnant NMRI mice were randomly assigned to each treatment group (eight mice per group) and injected subcutaneously once with either solvent (control), VPA at 1.8 or 3.6 mmol/kg, or an analogue of a VPA derivative at 1.8, 3.6, or 4.8 mmol/kg on GD 8.5 (10 a.m.) at a dosing volume of 10 mL/kg of body weight. The VPA dose levels used in this study have been known to be teratogenic in mice, and a dose level of approximately 3.6-4.8 mmol/kg was the maximum tolerated dose level (Kao et al, 1981;Menegola et al, 1996Menegola et al, , 1998Okada et al, 2004Okada et al, , 2008. With regard to new analogues of VPA urea derivatives, a preliminary study using non-pregnant mice found that none of the animals died after a single subcutaneous dosing at 4.8 mmol/kg of VCU, EHU, EMPU, or MBU.…”