Prevention of Phenytoin-Induced Gingival Overgrowth by Lovastatin in Mice

Abstract

Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required.

4PBA strongly attenuates endoplasmic reticulum stress, fibrosis, and mitochondrial apoptosis markers in cyclosporine treated human gingival fibroblasts

“…We experimented using three drugs: first, a chemical chaperone 4phenyl butyric acid (4PBA) which is an ER stress antagonist. second, an antioxidant melatonin that we earlier noticed was attenuating AOPP levels in gingival fibroblasts: Assaggaf, Kantarci, Sume, and Trackman () observed statin inhibiting CTGF and EMT in mice phenytoin induced overgrowth. Based on this study report, we included simvastatin as the third drug.…”

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB

“…Tissue blocks from three to five biopsies from different donors corresponding to dysplasia, differentiated OSCC, and poorly differentiated oral cancer, respectively, from the Boston University School of Dental Medicine Pathology diagnostic services laboratory were obtained under an approved IRB protocol (#31869). Sections (6 µm) were stained with hematoxylin and eosin, or immunostained for LOX or LOXL2 with counterstaining with hematoxylin 16,17 .…”

Treatment of Gingival Enlargement

“…Alternative medications to the anticonvulsant phenytoin include carbamazepine and valproic acid, both of which have been reported to induce gingival enlargement to a lesser degree. A murine study suggested that lovastatin may attenuate the onset of gingival enlargement induced by phenytoin [28]. Further research is necessary to confirm the therapeutic value of lovastatin.…”