Research Report Microglial involvement in neuroprotection following experimental traumatic brain injury in heat-acclimated mice Na'ama A. Shein a,b , Nikolaos Grigoriadis c , Michal Horowitz b, ⁎ , Gali Umschwief a,b , Alexander G. Alexandrovich a , Constantina Simeonidou d , Savvas Grigoriadis e , Olga Touloumi c , Esther Shohami a, ⁎ a Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Israel b Department of Physiology, The Hebrew University, Jerusalem, Israel c Department of Neurology, AHEPA University Hospital and Aristotle University, Thessaloniki, Greece d Department of Physiology, AHEPA University Hospital and Aristotle University, Thessaloniki, Greece e Department of Neurosurgery, Hebrew University Hadassah University Hospital, Jerusalem, Israel ARTICLE INFO ABSTRACT Article history: Accepted 6 September 2008 Available online 19 September 2008 Brain-derived neurotrophic factor (BDNF) conveys neuroprotection in various settings of experimental central nervous system injury. Using a model of endogenous neuroprotection, induced in mice by chronic exposure to moderate ambient heat (heat acclimation, HA), we have previously shown that neuroprotection following traumatic brain injury involves reduced post-injury tumor necrosis factor alpha (TNFα) expression. As glial cells play a pivotal role in post-injury inflammation on one hand, and are also capable of inducing neuroprotection by harboring trophic factors and BDNF in particular, the effects of injury and HA on overall BDNF content at the trauma area, gliosis and glial BDNF expression were investigated. Western blotting indicated higher overall BDNF levels in HA sham-operated mice. Following injury, a decrease was observed in the HA group only, reaching levels similar to normothermic mice. Immunohistochemical studies demonstrated BDNF-positive resting microglia in non-injured HA but not normothermic animals. Post-injury astrocytosis and microglial immunoreactivity were enhanced in the HA group. Particularly, an increase in the amount of ramified microglia was observed within the penumbra, accompanied by a concomitant decrease in globular microglia, a major source of pro-inflammatory mediators. BDNF labeling on and around microglia and their processes was intensified in HA mice. Furthermore, BDNF immunoreactivity in HA mice was evident in the degenerated edges of axons. These findings, taken together with the growing body of evidence indicating the neuroprotective potential of both BDNF and microglia, suggest a possible role of these cells in HA-induced neuroprotection. © 2008 Elsevier B.V. All rights reserved. Keywords: Cytokines Glia Neuroprotection Neurotrophin Preconditioning BRAIN RESEARCH 1244 (2008) 132 – 141 ⁎ Corresponding authors. Esther Shohami is to be contacted at fax: +972 2 675 8741. M. Horowitz, Laboratory of Environmental Physiology, The Hebrew University of Jerusalem, Israel. Fax: +972 2 643 9736. E-mail addresses: horowitz@cc.huji.ac.il (M. Horowitz), esty@cc.huji.ac.il (E. Shohami). Abbreviations: APP, amyloid precursor protein; ANOVA, analysis of variance; BDNF, brain-derived neurotrophic factor; CHI, closed head injury; DAB, 3,3′-diaminobenzidine; DAPI, 4′6-diamidino-2-phenylindole; GFAP, glial fibrillary acidic protein; HA, heat acclimation; IL-10, interleukin 10; TBI, traumatic brain injury; TNFα, tumor necrosis factor alpha 0006-8993/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2008.09.032 available at www.sciencedirect.com www.elsevier.com/locate/brainres