A peptide agonist of the neural cell adhesion molecule (NCAM), C3, protects against developmental defects induced by a teratogen pyrimethamine.
The neural cell adhesion molecule, NCAM, not only plays an important role in neuronal migration, differentiation and formation of connections in the developing nervous system, but also in the condensation of the mesodermal mesenchyme of the limb bud. Therefore, NCAM may be regarded as a target molecule for preventive strategies aimed at minimizing the effects of teratogens affecting the prenatal development of the nervous system and the skeleton. Treatment of fetuses with the teratogen pyrimethamine results in a reduced body weight, microcephaly and malformations of the hind limbs and forelimbs, e.g. micromelia, brachydactyly and adactyly. We here show that a peptide agonist of NCAM, C3, partly prevented the defects induced by this treatment. Although intra-amniotic administration of C3 at gestational day 14 had no effect on the pyrimethamine-induced reduction in body weight, it rescued the deficit in brain weight (microcephaly), partly reversed a decrease in thickness of the cortical plate, and significantly reduced the number of malformed fetuses. In vitro, C3 promoted survival of PC12-E2 cells treated with pyrimethamine. Since C3 is a peptide mimetic of NCAM, our data strongly suggest that stimulating of NCAM results in neuroprotection in vivo and in vitro.
Klementiev
Boris
B
Protein Laboratory, Institute of Molecular Pathology, Panum Institute Building 6.2., University of Copenhagen, Blegdamsvej 3C, Denmark. klement@plab.ku.dk
Bichevaja
Natalia
N
Novikova
Tatiana
T
Chebotar
Nikolaj
N
Bock
Elisabeth
E
Berezin
Vladimir
V
D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000002:abnormalities* / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D007267:Injections; D019006:Neural Cell Adhesion Molecules / Q000819:agonists*; D009929:Organ Size; D016716:PC12 Cells; D010455:Peptides; D011247:Pregnancy; D011256:Pregnancy Outcome; D011739:Pyrimethamine; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013723:Teratogens / Q000633:toxicity
C471108:C3 synthetic NCAM-ligand; D015816:Cell Adhesion Molecules, Neuronal; D019006:Neural Cell Adhesion Molecules; D010455:Peptides; D013723:Teratogens; D011739:Pyrimethamine