Induction of Cerebral Ischemic Tolerance by Erythromycin Preconditioning Reprograms the Transcriptional Response to Ischemia and Suppresses Inflammation

Abstract

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.

Neuroprotection Induced In Vitro by Ischemic Preconditioning and Postconditioning: Modulation of Apoptosis and PI3K–Akt Pathways

“…In contrast to the findings of Stenzel-Poore et al (2003) and Koerner et al (2007), we found a modestly higher proportion of upregulated than downregulated genes in the preconditioning-treated groups after both 3-h and 16-h reperfusions. This disparity is likely due to either the focus of our expression analyses on the apoptosis and PI3K-Akt pathway-associated genes as opposed to a global gene expression analysis or due to the use of a homogeneous in vitro culture sample.…”

“…Global gene expression studies using in vivo models of preconditioning have shown that, while ischemia alone induces an overall upregulation of gene expression, the pattern in preconditioned brains is one of widespread downregulation (Stenzel-Poore et al 2003;Koerner et al 2007). In contrast to the findings of Stenzel-Poore et al (2003) and Koerner et al (2007), we found a modestly higher proportion of upregulated than downregulated genes in the preconditioning-treated groups after both 3-h and 16-h reperfusions.…”

“…The mechanisms of preconditioning-induced tolerance are not well known, but have been shown to share three characteristic features. Ischemic tolerance involves de novo protein synthesis (Barone et al 1998), is correlated with overall repressed gene expression (Bowen et al 2006;Koerner et al 2007;Stenzel-Poore et al 2003), and is transient (Chen et al 1996;Perez-Pinzon et al 1997). The molecular changes underlying this ischemic tolerance may be effective against deleterious processes that occur during, or after, the injurious ischemia.…”

Protecting the brain during cardiac surgery: Does understanding the molecular mechanisms of cerebral injury provide insight for neuroprotection strategies

“…Pre-ischemic conditioning has long been recognised as a powerful 23,31 . Erythromycin is a highly promising candidate for clinical application as a tolerance-inducing drug in conditions with high risk for cerebral ischemia, such as during surgery.…”

“…Despite erythromycin's ability to affect cerebral ischemic tolerance, the molecular mechanisms that underlie this pharmacological tolerance induction have yet to be identified. Sustained preconditioning regimens have been associated with de novo protein synthesis via adapted gene transcription, suggesting that erythromycin may act at the transcriptional level 23,31 .…”