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Myo-inositol enhances teratogenicity of valproic acid in the mouse. 2006

Valentina Massa, and Bogdan Wlodarczyk, and Erminio Giavini, and Richard H Finnell
Department of Biology, University of Milan, Milan, Italy. valentinamassa@yahoo.it

BACKGROUND Valproic acid (VPA) is an anticonvulsant drug that is widely used therapeutically for a variety of neurological conditions. VPA is also well known for its teratogenic potential in both humans and experimental animal models. The typical malformations observed following VPA exposure include neural tube defects (NTDs) and craniofacial and skeletal malformations. Nevertheless, the mechanisms underlying VPA's anticonvulsant efficacy or its teratogenicity remain to be elucidated. It was recently suggested that a relationship exists between VPA exposure and the cellular depletion of myo-inositol (INO). Furthermore, INO has been shown to rescue NTDs in the curly tail mouse. The aim of this study was to investigate the interactions of VPA and INO in the developing embryo. METHODS For this purpose, 2 strains of mice were used: SWV/Fnn (known to be sensitive to VPA) and LM/Bc (known to be resistant to VPA-induced NTDs). Pregnant females were randomly assigned to 4 experimental groups: control, VPA (600 mg/kg), INO (400 mg/kg), and VPA plus INO. VPA was injected IP at 8.5 days postcoitum (dpc). INO was administered PO twice a day from 6.5 to 10.5 dpc. At term the dams were killed, the uteri were removed, and all of the general toxicological parameters (number of implants, resorptions, dam weight, and fetus weight) were recorded and statistically analyzed. RESULTS Postimplantation loss in the SWV/Fnn strain and NTDs in the LM/Bc strain were significantly increased after the coadministration of VPA and INO. CONCLUSIONS This work clearly indicates that INO enhances VPA-induced teratogenicity in the mouse.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D007294 Inositol An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. Myoinositol,Chiro-Inositol,Mesoinositol,Chiro Inositol
D008815 Mice, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations, or by parent x offspring matings carried out with certain restrictions. All animals within an inbred strain trace back to a common ancestor in the twentieth generation. Inbred Mouse Strains,Inbred Strain of Mice,Inbred Strain of Mouse,Inbred Strains of Mice,Mouse, Inbred Strain,Inbred Mouse Strain,Mouse Inbred Strain,Mouse Inbred Strains,Mouse Strain, Inbred,Mouse Strains, Inbred,Strain, Inbred Mouse,Strains, Inbred Mouse
D009436 Neural Tube Defects Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy generally occurring between days 18-29 of gestation. Ectodermal and mesodermal malformations (mainly involving the skull and vertebrae) may occur as a result of defects of neural tube closure. (From Joynt, Clinical Neurology, 1992, Ch55, pp31-41) Craniorachischisis,Developmental Defects, Neural Tube,Diastematomyelia,Exencephaly,Neurenteric Cyst,Spinal Cord Myelodysplasia,Tethered Cord Syndrome,Acrania,Developmental Neural Tube Defects,Iniencephaly,Neural Tube Developmental Defects,Neuroenteric Cyst,Occult Spinal Dysraphism,Occult Spinal Dysraphism Sequence,Tethered Spinal Cord Syndrome,Acranias,Craniorachischises,Cyst, Neurenteric,Cyst, Neuroenteric,Cysts, Neurenteric,Cysts, Neuroenteric,Defect, Neural Tube,Defects, Neural Tube,Diastematomyelias,Dysraphism, Occult Spinal,Dysraphisms, Occult Spinal,Exencephalies,Iniencephalies,Myelodysplasia, Spinal Cord,Myelodysplasias, Spinal Cord,Neural Tube Defect,Neurenteric Cysts,Neuroenteric Cysts,Occult Spinal Dysraphisms,Spinal Cord Myelodysplasias,Spinal Dysraphism, Occult,Spinal Dysraphisms, Occult,Tethered Cord Syndromes
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D004357 Drug Synergism The action of a drug in promoting or enhancing the effectiveness of another drug. Drug Potentiation,Drug Augmentation,Augmentation, Drug,Augmentations, Drug,Drug Augmentations,Drug Potentiations,Drug Synergisms,Potentiation, Drug,Potentiations, Drug,Synergism, Drug,Synergisms, Drug
D005260 Female Females
D000014 Abnormalities, Drug-Induced Congenital abnormalities caused by medicinal substances or drugs of abuse given to or taken by the mother, or to which she is inadvertently exposed during the manufacture of such substances. The concept excludes abnormalities resulting from exposure to non-medicinal chemicals in the environment. Drug-Induced Abnormalities,Abnormalities, Drug Induced,Abnormality, Drug-Induced,Drug Induced Abnormalities,Drug-Induced Abnormality
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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