1. ¹Department of Neurology, University of California, San Francisco, California, USA
2. ²Department of Neurosurgery, University of California, San Francisco, California, USA
3. ³Department of Radiology, University of California, San Francisco, California, USA
4. ⁴Linco Research, Inc., St. Charles, Missouri, USA
5. ⁵Department of Pediatrics, University of California, San Francisco, California, USA

Correspondence: Dr Zinaida S Vexler, Department of Neurology, University of California, Box 0663, 521 Parnassus Ave., San Francisco, CA 94143-0663, USA. E-mail: zinaida@itsa.ucsf.edu

Received 1 October 2004; Revised 11 November 2004; Accepted 24 November 2004; Published online 4 May 2005.

Abstract

The incidence of neonatal stroke is high and currently there are no strategies to protect the neonatal brain from stroke or reduce the sequelae. Agents capable of modifying inflammatory processes hold promise. We set out to determine whether delayed administration of one such agent, minocycline, protects the immature brain in a model of transient middle cerebral artery (MCA) occlusion in 7-day-old rat pups. Injury volume in minocycline (45 mg/kg/dose, beginning at 2 h after MCA occlusion) and vehicle-treated pups was determined 24 h and 7 days after onset of reperfusion. Accumulation of activated microglia/macrophages, phosphorylation of mitogen-activated protein kinase (MAPK) p38 in the brain, and concentrations of inflammatory mediators in plasma and brain were determined at 24 h. Minocycline significantly reduced the volume of injury at 24 h but not 7 days after transient MCA occlusion. The beneficial effect of minocycline acutely after reperfusion was not associated with changed ED1 phenotype, nor was the pattern of MAPK p38 phosphorylation altered. Minocycline reduced accumulation of IL-1 and CINC-1 in the systemic circulation but failed to affect the increased levels of IL-1, IL-18, MCP-1 or CINC-1 in the injured brain tissue. Therefore, minocycline provides early but transient protection, which is largely independent of microglial activation or activation of the MAPK p38 pathway.