Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 30, Issue 1, Pages 119-129Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2009.194
Keywords
asphyxia; chemokine; global ischemia; immature brain; inflammation
Categories
Funding
- American Heart Association [0535365N]
- NIH [NS061817, NS30318, HD057587, HD045968]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD045968, R21HD057587] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS061817, P01NS030318, P20NS030318, P50NS030318] Funding Source: NIH RePORTER
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The mechanisms leading to delayed neuronal death after asphyxial cardiac arrest (ACA) in the developing brain are unknown. This study aimed at investigating the possible role of microglial activation in neuronal death in developing brain after ACA. Postnatal day-17 rats were subjected to 9 mins of ACA followed by resuscitation. Rats were randomized to treatment with minocycline, (90mg/kg, intraperitoneally (i.p.)) or vehicle (saline, i.p.) at 1 h after return of spontaneous circulation. Thereafter, minocycline (22.5 mg/kg, i.p.) was administrated every 12 h until sacrifice. Microglial activation (evaluated by immunohistochemistry using ionized calcium-binding adapter molecule-1 (Iba1) antibody) coincided with DNA fragmentation and neurodegeneration in CA1 hippocampus and cortex (assessed by deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), Fluoro-Jade-B and Nissl stain). Minocycline significantly decreased both the microglial response and neuronal degeneration compared with the vehicle. Asphyxial CA significantly enhanced proinflammatory cytokine and chemokine levels in hippocampus versus control (assessed by multiplex bead array assay), specifically tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1 alpha (MIP-1 alpha), regulated upon activation, normal T-cell expressed and secreted (RANTES), and growth-related oncogene (GRO-KC) (P < 0.05). Minocycline attenuated ACA-induced increases in MIP-1 alpha and RANTES (P < 0.05). These data show that microglial activation and cytokine production are increased in immature brain after ACA. The beneficial effect of minocycline suggests an important role for microglia in selective neuronal death after pediatric ACA, and a possible therapeutic target. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 119-129; doi: 10.1038/jcbfm.2009.194; published online 16 September 2009
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