Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

Abstract

ackground: Matrix metalloproteinase (MMP) inhibi-tors decrease inflammation in normal tissues and sup-press cancer progress in normal tissues. Valproic acid (VA) and doxycycline (DX) are MMP inhibitors that have radio-protective effects. Their ability to inhibit MMPs in irradiated tissue is unknown and the role of MMPs in radio-protective effects has not been tested to date.Aims: The purpose of this study was to examine wheth-er administration of VA and DX to rats before irradia-tion affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition.Study Design: Animal experimentation.Methods: Twenty-six Wistar rats were randomized into four groups: control (CTRL), radiation (RT), VA plus radiation (VA+RT), and DX plus radiation (DX+RT).Three study groups were exposed to a single dose of abdominal 10 Gy gamma radiation; the CTRL group received no radiation. Single doses of VA 300 mg/kg and DX 100 mg/kg were administered to each rat be-fore radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue sam-ples were taken for analyses. Levels of inflammatory cytokines (TNF-?, IL-1?, and IL-6) and matrix metal-loproteinases (MMP-2 and MMP 9) were measured by ELISA, MMP activities were measured by gelatin and casein zymography and apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay.Results: VA decreased the levels of TNF-? and IL-1? proteins insignificantly and decreased apoptosis sig-nificantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activi-ties, which decreased in response to irradiation. No ef-fect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis.Conclusion: Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in early radiation and these ef-fects are independent from MMP inhibition