title: Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage.
abstract: BACKGROUND
  Matrix metalloproteinase (MMP) inhibitors decrease inflammation in normal tissues and suppress 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.
  
  
  OBJECTIVE
  The purpose of this study was to examine whether administration of VA and DX to rats before irradiation affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition.
  
  
  METHODS
  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 before radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue samples were taken for analyses. Levels of inflammatory cytokines (TNF-α, IL-1β, 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-α and IL-1β proteins insignificantly and decreased apoptosis significantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activities, which decreased in response to irradiation. No effect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis.
  
  
  CONCLUSIONS
  Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in early radiation and these effects are independent from MMP inhibition.
authors.affiliation: Department of General Surgery, Bozyaka Training and Research Hospital, İzmir, Turkey.
authors.forename: Ferda
authors.initials: F
authors.lastname: Hoşgörler
authors.affiliation: Department of Medical Biochemistry, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Didem
authors.initials: D
authors.lastname: Keleş
authors.affiliation: Department of Molecular Medicine, Dokuz Eylül University Health Science Institute, İzmir, Turkey.
authors.forename: Serpil
authors.initials: S
authors.lastname: Tanrıverdi-Akhisaroğlu
authors.affiliation: Department of Medical Biochemistry, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Şeniz
authors.initials: Ş
authors.lastname: İnanç
authors.affiliation: Department of Physiology, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akhisaroğlu
authors.affiliation: Department of Histology and Embryology, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Ülker
authors.initials: Ü
authors.lastname: Cankurt
authors.affiliation: Department of Pathology, Dr. Suat Seren Teaching Hospital, İzmir, Turkey.
authors.forename: Zekiye
authors.initials: Z
authors.lastname: Aydoğdu
authors.affiliation: Department of General Surgery, Bozyaka Training and Research Hospital, İzmir, Turkey.
authors.forename: Ahmet Deniz
authors.initials: AD
authors.lastname: Uçar
authors.affiliation: Department of Radiation Oncology, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Oğuz
authors.initials: O
authors.lastname: Çetinayak
authors.affiliation: Department of Medical Biochemistry, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Gülgün
authors.initials: G
authors.lastname: Oktay
authors.affiliation: Department of Physiology, Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Sevil Gönenç
authors.initials: SG
authors.lastname: Arda
keywords: Matrix metalloproteinase; doxycycline; radiation; valproic acid