Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats.

Abstract

BACKGROUND:

Ischemic postconditioning (IPOC), or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats.

METHODOLOGY/PRINCIPAL FINDINGS:

A focal cerebral ischemic model with permanent middle cerebral artery (MCA) occlusion plus transient common carotid artery (CCA) occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA) attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC.

CONCLUSIONS/SIGNIFICANCE:

The present study suggests that inhibition of the autophagic pathway plays a key role in IPOC-induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke.

• Authors: Li Gao, Teng Jiang, Jun Guo, Yi Liu, Guiyun Cui, Lize Gu, Lingying Su, Yingdong Zhang
• Journal: PloS one (PLoS One) Vol. 7 Issue 9 Pg. e46092 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23029398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Beclin-1
• Becn1 protein, rat
• Immunosuppressive Agents
• LC3 protein, rat
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins c-bcl-2
• 3-methyladenine
• Adenine
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Apoptosis Regulatory Proteins (genetics)
• Autophagy (drug effects)
• Beclin-1
• Brain (blood supply, drug effects, pathology)
• Brain Ischemia (genetics, pathology, prevention & control)
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Ischemic Postconditioning (methods)
• Male
• Microtubule-Associated Proteins (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Rats
• Rats, Sprague-Dawley
• Sirolimus (pharmacology, therapeutic use)
• Up-Regulation (drug effects)