Koerner Ines P, Gatting Matthias, Noppens Ruediger, Kempski Oliver, Brambrink Ansgar M
Department of Anesthesiology and Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz, Germany.
Anesthesiology. 2007 Mar;106(3):538-47. doi: 10.1097/00000542-200703000-00019.
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.
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.
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.
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.
单剂量大环内酯类抗生素红霉素可在体内诱导对脑缺血的耐受性（药物预处理）。本研究通过评估红霉素预处理对短暂性全脑缺血后脑转录反应的影响，确定了诱导耐受性的潜在机制。
对预处理和未预处理的大鼠进行15分钟的全脑缺血，通过互补DNA表达阵列鉴定脑基因表达的变化，并通过实时逆转录聚合酶链反应进行定量。
在该模型中，缺血导致未预处理脑中转录广泛上调。红霉素预处理诱导的耐受性逆转了这种模式，并导致大多数基因的净下调，有效地重新编程了大脑对缺血的反应模式。在预处理动物中发现的转录反应最显著变化是，全脑缺血原本会强烈诱导促炎基因，但预处理几乎完全抑制了这种诱导。相比之下，相同处理对缺血后凋亡诱导基因的表达影响很小。
这些发现为红霉素预处理诱导缺血耐受性提供了新的分子关联，并将进一步加深对这种临床上重要的新的预防性神经保护方案的理解。
