Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation.
BACKGROUND
A single dose of the macrolide antibiotic erythromycin can induce tolerance against cerebral ischemia in vivo (pharmacologic preconditioning). This study identified potential mechanisms of tolerance induction by assessing effects of erythromycin preconditioning on the cerebral transcriptional response to transient global cerebral ischemia.


METHODS
Preconditioned and nonpreconditioned rats were exposed to 15 min of global cerebral ischemia, and changes in cerebral gene expression were identified by complementary DNA expression array and quantified by real-time reverse-transcription polymerase chain reaction.


RESULTS
Ischemia caused a widespread up-regulation of transcription in nonpreconditioned brains in this model. Tolerance induction by erythromycin preconditioning reversed this pattern and caused a net down-regulation of a majority of genes, effectively reprogramming the brain's response pattern to ischemia. The most striking change in transcriptional response found in preconditioned animals was an almost complete suppression of the otherwise profound induction of proinflammatory genes by global ischemia. In contrast, the same treatment had little effect on the expression of apoptosis-inducing genes after ischemia.


CONCLUSIONS
These findings present a new molecular correlate for the induction of ischemic tolerance achieved by erythromycin preconditioning and will further the understanding of this clinically important new regimen of preemptive neuroprotection.
Koerner
Ines P
IP
Department of Anesthesiology and Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz, Germany.
Gatting
Matthias
M
Noppens
Ruediger
R
Kempski
Oliver
O
Brambrink
Ansgar M
AM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology*; D018076:DNA, Complementary / Q000187:drug effects; D004195:Disease Models, Animal; D004917:Erythromycin / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D018076:DNA, Complementary; D012333:RNA, Messenger; D004917:Erythromycin