Effects of PMA (PHORBOL-12-MYRISTATE-13-ACETATE) on the Developing Rodent Brain.
Perinatal infections have a negative impact on brain development. However, the underlying mechanisms leading to neurological impairment are not completely understood and reliable models of inflammation are urgently needed. Using phorbol-myristate-acetate as an activator of inflammation, we investigated the effect on the developing rodent brain. Neonatal rats and mice deficient in IL-18 or IRAK-4 were exposed to PMA. Brains were assessed for regulation of pro- and anti-inflammatory cytokines and cell death 24 hrs, 7 and 14 days after treatment. PMA induced an inflammatory response and caused widespread neurodegeneration in the brains of 3- and 7-day-old rats. In contrast, 14-day-old rats were resistant to the neurotoxic effect of PMA. Histological evaluation at the age of 14 and 21 days revealed a destruction of the cortical microstructure with decreased numerical density of neuronal cells. Mice deficient in IL-18 or IRAK-4 were protected against PMA induced brain injury. PMA treatment during a vulnerable period can alter brain development. IL-18 and IRAK-4 appear to be important for the development of PMA induced injury.
Department of Pediatrics I, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Mark
M
Dzietko
Department of Radiology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Maria
M
Hahnemann
Department of Neonatology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
Oliver
O
Polley
Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
Marco
M
Sifringer
Department of Pediatrics I, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Ursula
U
Felderhoff-Mueser
Department of Neonatology, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
Christoph
C
Bührer
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D001930:Brain Injuries / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics*; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D010703:Phorbol Esters / Q000633:toxicity; D011247:Pregnancy; D051381:Rats
D020382:Interleukin-18; D010703:Phorbol Esters; C119222:phorbol-12-myristate; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse