MicroRNA Linked to Severity of Stroke Damage to the Brain

A class of microRNAs has been identified that acts to minimize stroke damage to the brain by preventing the accumulation of extracellular glutamate by lowering the levels of glutamate receptor subunits.

MicroRNAs (miRNAs) are snippets of about 20 nucleotides that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA.

Glutamate (glutamic acid) is the most prominent neurotransmitter in the body, and it is the main excitatory neurotransmitter, being present in over 50% of nervous tissue. Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke and diseases such as amyotrophic lateral sclerosis, autism, some forms of mental retardation, and Alzheimer's disease.

Investigators at Johns Hopkins University (Baltimore, MD, USA) have now linked the extent of damage caused to the brain by a stroke to the activity of a specific microRNA, miR-223.

They reported in the November 13, 2012, issue of the journal Proceedings of the National Academy of Sciences of the United States of America that miR-223 controlled the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowered the levels of GluR2 and NR2B by targeting specific sites in GluR2 and NR2B. This caused the inhibition of calcium influx in hippocampal neurons and protected the brain from neuronal cell death following transient global ischemia.

MiR-223 deficiency resulted in higher levels of NR2B and GluR2, enhanced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 led to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity.

“We set out to find a small molecule with very specific effects in the brain, one that could be the target of a future stroke treatment,” said senior author Dr. Valina Dawson, professor of medicine at Johns Hopkins University. “What we found is this molecule involved in immune response, which also acts in complex ways on the brain. This opens up a suite of interesting questions about what microRNA-223 is doing and how, but it also presents a challenge to any therapeutic application.”

“Because miR-223 is involved in regulating so many different proteins, and because it affects glutamate receptors, which themselves are involved in many different processes, miR-223 is unlikely to become a therapeutic target in the near future unless researchers figure out how to avoid unwanted side effects,” said Dr. Dawson.

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