Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion

• Published in: Journal of cerebral blood flow and metabolism Vol. 25; no. 9; pp. 1138 - 1149
• Main Authors: Fox, Christine, Dingman, Andra, Derugin, Nikita, Wendland, Michael F, Manabat, Catherine, Ji, Shaoquan, Ferriero, Donna M, Vexler, Zinaida S
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-09-2005; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Biological and medical sciences; Brain - pathology; Brain Chemistry - drug effects; Brain Chemistry - physiology; Chemokines - metabolism; Cytokines - metabolism; Enzyme Activation - physiology; Female; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Immunohistochemistry; Macrophage Activation - physiology; Medical sciences; Minocycline - pharmacology; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Vascular diseases and vascular malformations of the nervous system; MAPK p38; neonatal stroke; chemokine; inflammation; microglia; minocycline; Human; Stroke; Nervous system diseases; Enzyme; Tetracycline derivatives; Ischemia reperfusion; Mitogen-activated protein kinase; Cardiovascular disease; Inflammation; Cerebral disorder; Microglia; Vascular disease; Antibiotic; Newborn; Central nervous system disease; Brain ischemia; Minocycline; Antibacterial agent; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/sj.jcbfm.9600121

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-1β and CINC-1 in the systemic circulation but failed to affect the increased levels of IL-1β, 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.