Restoring neurons to preserve memory after heart attack or stroke

People who suffer from heart attacks or strokes face a high risk of memory loss, because when fresh blood stops flowing in the brain, neurons in a region of the hippocampus involved in memory can die. Now, Stanford University researchers are proposing a new strategy for helping the brain recover those brain cells—and it involves controlling the activation of genes that can coax surrounding cells to transform into neurons.

The team showed that blocking a particular microRNA in rat models changes the process by which genes produce proteins in the brain. That affects astrocytes, which are star-shaped cells that support neurons and that comprise about half of the brain’s cells. Specifically, blocking the microRNA can prompt the astrocytes to become neurons. They published the finding in the journal eNeuro.

The microRNA that the Stanford researchers blocked, called miR-181a, builds up in the brain after an event that causes a massive drop in blood flow such as a heart attack or stroke. The researchers had previously shown they could use a drug to block miR-181 before such an event and prevent neurons from dying in rats.

Of course, that approach wouldn’t be much use to people, so the team set out to study whether blocking miR-181a after trauma had occurred in the brain would also work. First, they induced very low blood pressure in the rodent models, causing 95% of the neurons in the hippocampus’ memory center to die. Then they injected the miR-181a-blocking drug directly into the animals’ hippocampi either two hours later or a full week later.

All of the rats that were injected with the drug showed higher levels of neuron regeneration than animals that got a control molecule did, the researchers reported.

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The Stanford researchers were surprised by the results, because neural stem cells typically don’t generate new neurons during adulthood in the particular region of the hippocampus they were studying. When that region becomes damaged, astrocytes flood in to support connections between the remaining neurons.

So, they decided to track the astrocytes by labeling both them and the neurons with different fluorescent tags. That’s how they discovered that some of the astrocytes seemed to be changing into neurons.

Astrocytes have become popular targets for scientists searching for new methods for regenerating neurons. Last year, a team at UT Southwestern, for example, zeroed in on the gene LZK and discovered that when they overexpressed it, they could boost the number of astrocytes that responded to brain and spinal cord injuries. Dialing up the gene, they proposed, could speed the recovery from those injuries.

Meanwhile, several companies are pouring resources into the search for new stroke treatments. Among them is Biogen, which optioned a drug from TMS last year that’s designed to inhibit inflammation in areas of the brain affected by a sudden loss of fresh blood flow. That deal could be worth up to $335 million to TMS.

The Stanford researchers are optimistic that targeting astrocytes by blocking miRNA-181a could prove a viable strategy, and they have a plan in place for proving out the concept. They are currently designing further experiments to confirm that some astrocytes are indeed turning into neurons. They also plan to study whether blocking the microRNA in rats helps them recover memory and learning after a brain injury.

Senior author Creed Stary, M.D., Ph.D., assistant professor of anesthesiology, perioperative and pain medicine, believes the study shows the potential for using a drug to help the hippocampus recover after a stroke or heart attack. “It points toward blocking the microRNA being a protective agent itself, but also provides insight to identify new therapeutic gene targets,” he said in a statement.