Minocycline Confers Early but Transient Protection in the Immature Brain following Focal Cerebral Ischemia—Reperfusion

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

Minocycline Reduces Neuronal Death and Attenuates Microglial Response after Pediatric Asphyxial Cardiac Arrest

“…In line with this, minocycline treatment has been shown to attenuate neuroinflammation and improve neurobehavioral performance after unilateral carotid artery ligation and hypoxia model in PND3 to PND7 rats (Carty et al, 2008;Fan et al, 2006;Lechpammer et al, 2008;Leonardo et al, 2008). However, the beneficial effects of minocycline likely depend on the type of insult, since its protective effects were reported to be transient after middle cerebral artery occlusion in PND7 rats (Fox et al, 2005). To our knowledge, our investigation is the first study evaluating the effect of minocycline after ACA in the immature brain.…”

Lithium-Mediated Long-Term Neuroprotection in Neonatal Rat Hypoxia–Ischemia is Associated with Antiinflammatory Effects and Enhanced Proliferation and Survival of Neural Stem/Progenitor Cells

“…Evidence suggests that neuroinflammation is a negative regulator of neurogenesis (Monje et al, 2003). Furthermore, treatment with minocycline after HI reduced microglia activation and injury in the immature brain (Arvin et al, 2002;Cai et al, 2006;Fox et al, 2005) although conflicting reports exist (Tsuji et al, 2004). Further work is needed to elucidate the roles of microglia and consequences of inflammation after HI, but injury-induced inflammation may be an important target for therapeutic interventions.…”

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

“…58 However, unlike in the adult, this protection is not sustained over time. 59 Such findings serve to emphasize the unique response of the developing brain to injury and remind us that the neuroprotective effects of a particular drug in the injured adult brain may not be predictive of its action in the immature brain. Any potential therapeutic agent must therefore be carefully evaluated in this context.…”