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Strategies for Study of Neuroprotection from Cold-preconditioning
Published on: September 2, 2010
Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways
Ashutosh Dharap1, Raghu Vemuganti
1Department of Neurological Surgery and Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53792, USA.
Abstract:
Cerebral gene expression is known to be significantly influenced by a sublethal ischemic event (pre-conditioning; PC) that induces tolerance to future damaging ischemic events. Small non-coding RNAs known as microRNAs (miRNAs) were recently shown to control the mRNA translation. We currently profiled cerebral miRNAs in the cerebral cortex of rats subjected to PC. The miRNAome reacted quickly and by 6 h following PC, levels of 51 miRNAs were altered (26 up- and 25 down-regulated; > 1.5-fold change). Twenty of these stayed at the altered level even at 3 days after PC. At least nine miRNAs showed > 5-fold change at one or more time points between 6 h to 3 days after PC compared with sham. Bioinformatics analysis showed 2007 common targets of the miRNAs that were up-regulated and 459 common targets of the miRNAs that were down-regulated after PC. Pathways analysis showed that MAP-kinase and Mammalian target of rapamycin (mTOR) signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the up-regulated miRNAs, and Wnt and GnRH signaling are the top two Kyoto Encyclopedia of Genes and Genomes pathways targeted by the down-regulated miRNAs after PC. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction of ischemic tolerance.
Insights
Pre-conditioning (PC) alters cerebral microRNAs (miRNAs) rapidly, with many changes persisting for days. These miRNA alterations in signaling pathways may induce ischemic tolerance, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Sublethal ischemic events (pre-conditioning) induce cerebral tolerance to subsequent ischemia.
- MicroRNAs (miRNAs) are small non-coding RNAs regulating mRNA translation and gene expression.
- Understanding miRNA changes after pre-conditioning is crucial for elucidating ischemic tolerance mechanisms.
Purpose of the Study:
- To profile cerebral microRNA expression in rats following pre-conditioning (PC).
- To identify specific miRNAs and their target pathways involved in inducing ischemic tolerance.
Main Methods:
- Cerebral cortex miRNA profiling in rats subjected to PC.
- Bioinformatics analysis to identify miRNA targets and associated signaling pathways (KEGG).
- Quantitative analysis of miRNA expression levels at 6 hours and 3 days post-PC.
Main Results:
- Rapid and significant alterations in 51 cerebral miRNAs were observed within 6 hours of PC.
- Twenty miRNAs remained altered at 3 days post-PC, with nine showing >5-fold change.
- Bioinformatics identified numerous mRNA targets and highlighted MAP-kinase, mTOR, Wnt, and GnRH signaling pathways.
Conclusions:
- Pre-conditioning induces rapid and sustained changes in the cerebral miRNAome.
- Altered miRNAs and their downstream targets in key signaling pathways likely contribute to the development of ischemic tolerance.
- These findings suggest miRNAs as potential therapeutic targets for stroke prevention.
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