title: Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury.
abstract: OBJECTIVE
  Inflammation promotes epidermal wound healing but is considered detrimental to recovery from central nervous system injury. Sick infants have increased levels of cytokines in their cerebrospinal fluid that correlate with poor neurological outcome. In this study, we investigated the role of neuroinflammation and more specifically interleukin 6 (IL-6) in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury.
  
  
  METHODS
  Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups, and IL-6 was quantified with or without indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and leukemia-inhibiting factor (LIF) affect SVZ cell expansion, proliferation, and self-renewal.
  
  
  RESULTS
  Consistent with earlier studies, medially situated SVZ cells expanded after H/I. Contrary to our expectations, indomethacin significantly decreased both the initial reactive increase in these precursors and their ability to self-renew. By contrast, indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal, and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using prostaglandin E2, which is downstream of cyclooxygenase 2 and a target of indomethacin.
  
  
  CONCLUSIONS
  These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons.
authors.affiliation: Department of Neurology and Neurosciences, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 205 South Orange Avenue, Newark, NJ 07103, USA.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Covey
authors.forename: Dean
authors.initials: D
authors.lastname: Loporchio
authors.forename: Krista D
authors.initials: KD
authors.lastname: Buono
authors.forename: Steven W
authors.initials: SW
authors.lastname: Levison
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002552:Cerebral Ventricles / Q000166:cytology* / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D007213:Indomethacin