Progenitor cell injury after irradiation to the developing brain can be modulated by mild hypothermia or hyperthermia Aya Fukuda,* ,  Hirotsugu Fukuda,* ,  Marie Jo ¨nsson,* Janos Swanpalmer,à Sven Hertzman,à Birgitta Lannering,§ Thomas Bjo ¨rk-Eriksson,¶ Ildiko ´ Ma `rky§ and Klas Blomgren* , § *The Arvid Carlsson Institute of Neuroscience at the Institute of Clinical Neuroscience, Sahlgrenska Academy, Go ¨teborg University, Go ¨teborg, Sweden  Department of Obstetrics and Gynecology, Osaka University School of Medicine, Suita, Japan àDepartment of Radiation Physics, Sahlgrenska University Hospital, Go ¨teborg, Sweden §Department of Pediatrics, The Queen Silvia Children’s Hospital, Go ¨teborg, Sweden ¶Department of Oncology, Sahlgrenska University Hospital, Go ¨teborg, Sweden Abstract Ionizing radiation induced acute cell death in the dentate gyrus subgranular zone (SGZ) and the subventricular zone (SVZ). Hypomyelination was also observed. The effects of mild hypothermia and hyperthermia for 4 h after irradiation (IR) were studied in postnatal day 9 rats. One hemisphere was irradiated with a single dose of 8 Gy and animals were rand- omized to normothermia (rectal temperature 36°C for 4 h), hypothermia (32°C for 4 h) or hyperthermia (39°C for 4 h). Cellular injury, e.g. chromatin condensation and nitrotyrosine formation, appeared to proceed faster when the body temperature was higher. Caspase-3 activation was more pronounced in the hyperthermia group and nuclear translo- cation of p53 was less pronounced in the hypothermia group 6 h after IR. In the SVZ the loss of nestin-positive progenitors was more pronounced (48%) and the size was smaller (45%) in the hyperthermia group 7 days post-IR. Myelination was not different after hypo- or hyperthermia. This is the first report to demonstrate that hypothermia may be beneficial and that hyperthermia may aggravate the adverse side-effects after radiation therapy to the developing brain. Keywords: apoptosis, developing brain, hyperthermia, hypothermia, neurogenesis, radiation therapy. J. Neurochem. (2005) 94, 1604–1619. Brain tumors constitute approximately one-third of all childhood cancers (Nordic Society of Pediatric Hematology and Oncology solid tumor registry report 2004), and radiation therapy (RT) is one of the most effective treatments for these malignancies. RT is applied to both adults and children who suffer from primary or metastatic tumors located within and close to the central nervous system (CNS), including CNS involvement of leukemia and lymphoma. However, damage to normal, surrounding tissue constitutes a major problem, and RT is associated with adverse side-effects, including intellectual impairment as well as perturbed growth and puberty (Lannering et al. 1990a,b, 1995; Hall et al. 2004; Spiegler et al. 2004). Significant intellectual or behavioral retardation was more severe in children less than 3 years of age at time of RT (Chin and Maruyama 1984; Li et al. 1984; Duffner et al. 1985; Packer et al. 1987). Even very low doses of ionizing radiation, such as those used earlier to treat cutaneous hemangiomas in children before 18 months of age, showed a negative correlation with intellectual capacity at 18–19 years of age (Hall et al. 2004). Received March 3, 2005; revised manuscript received April 23, 2005; accepted May 18, 2005. Address correspondence and reprint requests to Klas Blomgren, The Arvid Carlsson Institute, Go ¨teborg University, Box 432, SE 405 30 Go ¨teborg, Sweden. E-mail: klas.blomgren@neuro.gu.se. Abbreviations used: AIF, apoptosis-inducing factor; Dcx, doublecor- tin; DG, dentate gyrus (of the hippocampus); GCL, granular cell layer (of the DG); HI, hypoxia-ischemia; IOD, integrated optical density; IR, irradiation; MBP, myelin basic protein; P, postnatal day; PBS, phosphate- buffered saline; RT, radiation therapy; SGZ, subgranular zone (of the GCL); SVZ, subventricular zone. Journal of Neurochemistry , 2005, 94, 1604–1619 doi:10.1111/j.1471-4159.2005.03313.x 1604 Ó 2005 International Society for Neurochemistry, J. Neurochem. (2005) 94, 1604–1619