Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is

Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. injury was examined after these assessments. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes concentrations of IL-1β and TNFα and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure and the protective effects are associated with its anti-inflammatory properties. Keywords: lipopolysaccharide cyclooxygenase-2 celecoxib oligodendrocyte microglia astrocyte INTRODUCTION Increasing evidence has indicated that perinatal contamination or inflammation and hypoxia-ischemia are major contributors to perinatal brain injury such as periventricular leukomalacia (PVL) a predominant form of injury in the premature infant brain (Dammann and Leviton 1997 2004 Goldenberg et al. 2008 Hagberg et al. 2002 Volpe 2003 The intrinsic vulnerability of late oligodendrocyte (OL) progenitors (O4+/O1-) which are the predominant OL lineage during the peak period of PVL (i.e. 24-32 gestation weeks) is considered central to pathogenesis of PVL in the infant brain (Back et al. 2001 2002 Rezaie and Dean 2002 Elevated concentrations of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) are frequently observed in the brain (Kadhim et al. 2001 2003 Yoon et al. 1997 cord blood (Yoon et al. 1996 and amniotic fluid (Yoon et al. 1997 in infants with PVL. Therefore treatments aiming at anti-inflammation might provide protection to OLs. In our previous study we found that intracerebral (i.c.) injection of LPS resulted in acute white matter and neuronal injury in the neonatal rat (Cai et al. 2003 Fan et al. 2005 2008 Pang et al. 2003 Activation of microglia plays a critical role Erlotinib mesylate in neonatal i.c. LPS-induced brain injury in the rat brain (Fan et al. 2005 2008 Conversation of microglial cells with apoptotic neurons has been reported to selectively promote COX-2 expression and COX-2 may mediate microglial activation and may play a key role in amplifying the inflammatory response with toxic effects (Bartels and Leenders 2010 De Simone et al. 2004 Two COX isoforms have been characterized: COX-1 which is usually constitutively expressed in most tissues and is thought to mediate FOXO4 physiological responses and COX-2 which is Erlotinib mesylate usually rapidly expressed in several cell types in response to cytokines growth factors and pro-inflammatory Erlotinib mesylate molecules (Bartels and Leenders 2010 Choi et al. 2009 Minghetti 2004 In the central nervous system (CNS) the expression of COX-2 may contribute to fundamental brain functions; however COX-2 is usually induced in inflammatory cells in response to cytokines and pro-inflammatory molecules suggesting that COX-2 has a role in the inflammatory processes (Bartels and Leenders 2010 Minghetti 2004 Celecoxib is usually a selective COX-2 inhibitor currently being used in the treatment of various painful and inflammatory conditions and is the safest COX-2 inhibitor relating to the cardiovascular safety data (Jones 2005 Celecoxib may decrease the phosphorylation state of p38 and p44/42 of mitogen-activated Erlotinib mesylate protein kinase (MAPK) in human osteoarthritic chondrocytes (Takahashi et al. 2005 and celecoxib also can enhance heme oxygenase-1 (HO-1) mediated anti-inflammatory activity in vascular endothelium (Hamdulay et al. 2010 The neuroprotective action of celecoxib has been observed in Erlotinib mesylate the LPS-induced nigrostriatal neurodegeneration (Hunter et al. 2007 and.