The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning).
BACKGROUND
Cerebral ischemic tolerance can be induced by a variety of noxious stimuli, but no clinically applicable regimen for preconditioning has been described. Therefore, the authors tested the ability of a pharmacologic preconditioning strategy using the well-known macrolide antibiotic erythromycin to induce tolerance against transient global cerebral ischemia in vivo. They also investigated whether tolerance induction by erythromycin involves transcriptional and translational changes of cerebral B-cell leukemia/lymphoma-2 (bcl-2) expression.


METHODS
Male Wistar rats were treated with erythromycin (25 mg/kg intramuscularly) or vehicle and subjected to 15 min of transient global cerebral ischemia 6, 12, or 24 h after pretreatment. Neurologic deficit was evaluated once daily, and neuronal cell survival was assessed after 7 days of reperfusion. Additional animals were similarly pretreated, and cerebral bcl-2 messenger RNA (mRNA) and protein expression was analyzed 6 and 24 h later.


RESULTS
Erythromycin improved postischemic neuronal survival in hippocampal CA1 and CA3 sectors and reduced functional deficit, with 12 h being the most efficient pretreatment interval. Bcl-2 mRNA in hippocampus was transiently up-regulated 6 h after erythromycin, but neuronal Bcl-2 protein remained unchanged.


CONCLUSIONS
Erythromycin can induce cerebral ischemic tolerance in vivo (pharmacologic preconditioning), suggesting a potential clinical strategy of preemptive neuroprotection. Changes in bcl-2 expression after erythromycin were small and transient. The induction of bcl-2-related pathways, although important for other preconditioning regimens, may therefore be less relevant for the neuroprotective effects of pharmacologic preconditioning using erythromycin.
Brambrink
Ansgar M
AM
Department of Anesthesiology and Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University, Mainz, Germany. brambrin@ohsu.edu
Koerner
Ines P
IP
Diehl
Kathrin
K
Strobel
Georg
G
Noppens
Ruediger
R
Kempski
Oliver
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004917:Erythromycin / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D019194:Ischemic Preconditioning; D008297:Male; D009474:Neurons / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion
D000900:Anti-Bacterial Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D004917:Erythromycin