Neuro-cognitive disabilities are a well-recognized co
mplication of hypother
mic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and
microglial proliferation and activation that are only partially
mitigated by hypother
mia. Microglia, and possibly other cells, are suggested to elaborate tu
mor necrosis factor alpha (TNF-伪), which can trigger neuronal death cascades and exacerbate ede
ma after CNS insults. Minocycline is neuroprotective in so
me brain ische
mia
models in part by blunting the
microglial response. We tested the hypothesis that
minocycline would attenuate neuroinfla
mmation as reflected by brain tissue levels of TNF-伪 after hypother
mic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6
min nor
mother
mic CA. Hypother
mia (30 掳C) was then induced by an aortic saline flush. After a total of 20
min CA, resuscitation was achieved via cardiopul
monary bypass (CPB). After 5
min reperfusion,
minocycline (90
mg kg
鈭?;
m>nm> = 6) or vehicle (PBS;
m>nm> = 6) was given. Hypother
mia (34 掳C) was
maintained for 6 h. Rats were sacrificed at 6 or 24 h. TNF-伪 was quantified (ELISA) in four brain regions (cerebellu
m, CEREB; cortex, CTX; hippoca
mpus, HIP; striatu
m, STRI). Na茂ve rats (
m>nm> = 6) and rats subjected to the sa
me anesthesia and CPB but no CA served as controls (
m>nm> = 6). I
mmunocytoche
mistry was used to localize TNF-伪. Na茂ve rats and CPB controls had no detectable TNF-伪 in any brain region. CA
markedly increased brain TNF-伪. Regional differences were seen, with the highest TNF-伪 levels in striatu
m in CA groups (10-fold higher,
m>Pm> < 0.05 vs. all other brain regions). TNF-伪 was undetectable at 24 h. Minocycline attenuated TNF-伪 levels in CTX, HIP and STRI (
m>Pm> < 0.05). TNF-伪 showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-伪 levels after prolonged hypother
mic CA, with
maxi
mal increases in striatu
m. Surprisingly, TNF-伪 co-localized in neurons and not
microglia. Minocycline attenuated TNF-伪 by approxi
mately 50% but did not totally ablate its production. That
minocycline decreased brain TNF-伪 levels suggests that it
may represent a therapeutic adjunct to hypother
mia in CA neuroprotection.
University of Pittsburgh IACUC 0809278B-3.