title: Minocycline modulates cytokine and gene expression profiles in the brain after whole-body exposure to radiation.
abstract: An effective countermeasure against radiation damage to normal tissues is urgently needed. The major goal of the present study was to determine if minocycline could modify the immunomodulatory effects of radiation on the brain. C57BL/6 mice were treated with minocycline intraperitoneally for 5 days beginning immediately before total-body exposure to 0, 1, 2 and 3 Gray (Gy) (60)Co γ-rays. Brains were collected on days 4 and 32 post-irradiation for cytokine and gene analyses. Minocycline treatment significantly increased the levels of interleukin (IL)-10, IL-15 and vascular endothelial growth factor (VEGF) in the brain on day 4 in one or more irradiated groups compared to radiation-alone (p<0.05). IL-10 is anti-inflammatory, IL-15 can prevent apoptosis and VEGF is nuroprotective. On day 32, the drug decreased IL-1β in the 2- Gy group (p<0.05 vs. 2-Gy alone); this cytokine is implicated in immune-related central nervous system pathologies. Microarray analysis of brains on day 32 showed that while radiation increased expression of inflammatory genes such as Il1f10, Il17, Tnfrsf11b, Tnfsf12, Il12b and Il1f8, these were no longer up-regulated in the minocycline-treated groups. Similarly, the pro-apoptotic gene Bik and nitric oxide synthase producer (Nostrin) were no longer up-regulated in the drug-treated groups. Pathway analysis based on gene data suggested that catenin-β1 and tumor suppressor-related transcription regulation were significantly activated by radiation and/or minocycline (activation z-score >2.0). Overall, the data warrant further testing of minocycline as a potential neuroprotectant against radiation-induced damage.
authors.affiliation: Chan Shun Pavilion, Room A-1010, 11175 Campus Street, Loma Linda University, Loma Linda, CA 92354, U.S.A. dgridley@llu.edu.
authors.forename: Shalini
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pecaut
authors.forename: Daila S
authors.initials: DS
authors.lastname: Gridley
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects; D016753:Interleukin-10 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D051379:Mice; D008911:Minocycline / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D059467:Transcriptome / Q000187:drug effects / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014916:Whole-Body Irradiation
chemical_list: D019409:Interleukin-15; D018696:Neuroprotective Agents; D011837:Radiation-Protective Agents; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10; D008911:Minocycline
keywords: Gamma radiation; apoptosis; inflammation; mouse model; radioprotectant