Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration Nicole Bye a,b , Mark D. Habgood d , Jennifer K. Callaway e , Nakisa Malakooti a , Ann Potter d , Thomas Kossmann a,c , M. Cristina Morganti-Kossmann a,b, ⁎ a National Trauma Research Institute and Department of Trauma Surgery, Alfred Hospital, Victoria, Australia b Department of Medicine, Monash University, Victoria, Australia c Department of Surgery, Monash University, Victoria, Australia d Department of Pharmacology, University of Melbourne, Victoria, Australia e Brain Injury and Repair, Howard Florey Institute, Victoria, Australia Received 21 July 2006; revised 10 October 2006; accepted 25 October 2006 Available online 22 December 2006 Abstract Cerebral inflammation and apoptotic cell death are two processes implicated in the progressive tissue damage that occurs following traumatic brain injury (TBI), and strategies to inhibit one or both of these pathways are being investigated as potential therapies for TBI patients. The tetracycline derivative minocycline was therapeutically effective in various models of central nervous system injury and disease, via mechanisms involving suppression of inflammation and apoptosis. We therefore investigated the effect of minocycline in TBI using a closed head injury model. Following TBI, mice were treated with minocycline or vehicle, and the effect on neurological outcome, lesion volume, inflammation and apoptosis was evaluated for up to 7 days. Our results show that while minocycline decreases lesion volume and improves neurological outcome at 1 day post-trauma, this response is not maintained at 4 days. The early beneficial effect is likely not due to anti-apoptotic mechanisms, as the density of apoptotic cells is not affected at either time-point. However, protection by minocycline is associated with a selective anti-inflammatory response, in that microglial activation and interleukin-1β expression are reduced, while neutrophil infiltration and expression of multiple cytokines are not affected. These findings demonstrate that further studies on minocycline in TBI are necessary in order to consider it as a novel therapy for brain-injured patients. Crown Copyright © 2006 Published by Elsevier Inc. All rights reserved. Keywords: Apoptosis; Cytokines; Inflammation; Microglia; Minocycline; Traumatic brain injury Introduction Brain damage after traumatic brain injury (TBI) results from both the primary mechanical impact and secondary degenera- tive responses that occur in the minutes to days following trauma. Secondary processes involve diverse pathways, includ- ing profound cerebral inflammation, excitatory amino acid and calcium associated cytotoxicity, and ischemic events, all of which may lead to acute and chronic cell death and contribute to functional impairment (McIntosh et al., 1998; Raghupathi, 2004). The immune responses elicited after TBI involve the activation of resident glial cells, astrocytes and microglia, as well as blood leukocytes accumulated in the injured brain which in concert secrete soluble cytokines (Morganti-Kossmann et al., 2001). Cerebral inflammation can play dual opposing roles, on one hand by supporting processes of repair and on the other hand by exacerbating tissue damage. There is robust evidence Experimental Neurology 204 (2007) 220 – 233 www.elsevier.com/locate/yexnr ⁎ Corresponding author. National Trauma Research Institute and Department of Trauma Surgery, Alfred Hospital Department of Medicine, Monash University, Victoria, Australia. Fax: +61 3 9207 1811. E-mail address: cristina.morganti-kossmann@med.monash.edu.au (M.C. Morganti-Kossmann). 0014-4886/$ - see front matter. Crown Copyright © 2006 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.10.013