Cogram, P.; (2008) Inositol and protein kinase C in the prevention of neural tube defects. Doctoral thesis , University of London.

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Abstract

A number of mouse genetic mutants develop neural tube defects (NTDs). In some cases, defects can be prevented by administration of folic acid during pregnancy, whereas in other mutants there is no response. This parallels the human situation in which a proportion of NTDs appear resistant to folic acid therapy. Curly tail is the best characterised mouse model of folic acid-resistant NTDs. Previously it was shown that the incidence of spina bifida in curly tail mice can be reduced by administration of inositol during embryonic development. In this thesis, I compared the effectiveness of two isomers, myo- and D-chiro-inositol, with administration either directly to embryos in vitro, or to pregnant females by subcutaneous or oral routes. Although both inositols exerted a preventive effect on spina bifida, by all routes of administration, D-chiro-inositol consistently exhibited greater potency than myo-inositol. The protective effect of inositol has been shown previously to be mediated through the activity of the inositol/lipid cycle and to depend on downstream activation of protein kinase C (PKC). In the studies decscribed in this thesis, I examined the role of PKC in more detail. The expression of PKC isoforms was first examined by irrmiunohistochemistry, Broad spectrum chemical inhibitors were then used in whole embryo culture to confirm that one or more PKC isoforms are indispensable for normalisation of neural tube closure by inositol. Specific peptide inhibitors were then applied, and revealed that PKC beta I, gamma and zeta are most important in the protective pathway. Finally, I demonstrated that inositol stimulates cell proliferation in the hindgut of curly tail embryos, reversing the imbalance of cell proliferation that is known to lead, via enhanced ventral curvature of the caudal region, to delay or failure of neural tube closure.

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