MHC Molecules, Receptor Stymie Brain After Stroke
By Anette Breindl
Researchers have reported that knockout mice lacking either two specific types of major histocompatibility complex molecules or their receptor fared better after a stroke than their wild-type cousins.
In fact, lacking the MHC class I molecules Kb and Db, or their receptor PirB, improved "not only the amount of damage early on, but also what happens during recovery," co-corresponding author Rona Giffard told BioWorld Today. The findings were published in the March 22, 2012, issue of Neuron.
For now, there are no drugs that target either half of the receptor-ligand pair. But Giffard is optimistic that such drugs will come down the pike.
"People are interested in this not just for stroke," she said. "So I think these molecules will be coming along."
The reason for that more general interest is that MHC1 molecules, in addition to their roles in the brain, are immune system proteins that are important for antigen presentation.
In fact, MHC1 molecules were long thought to not exist in the brain at all. But roughly 15 years ago, experiments by co-corresponding author Carla Shatz and her colleagues showed that not only did those molecules exist in the brain, but some of them were specifically expressed on neurons, and that they are important for plasticity, that is, for adjusting the strength between neural connections. Both Shatz and Giffard are faculty members at Stanford University School of Medicine.
Such plasticity is critical to recovery after a stroke, as it enables still-healthy parts of the brain to take over functions from damaged parts. And so, Giffard, Shatz and their team decided to look at changes in MHC1 molecules after stroke.
They found that levels of Kb and Db rose in the brain after a stroke, and that animals lacking these molecules had a better recovery than normal animals.
To Giffard, the finding that MHC1 molecules are involved in stroke sequelae is encouraging from a targeting perspective. "The brain does change the levels of these molecules in response to stroke," she said, and so trying to inhibit their effects "would be targeting a deleterious pathway that is activated in stroke, not just adding on to what normally happens."
Given that MHC1 molecules have both brain and immune system functions, knockouts might have fared better because they had no receptors in the brain – or because those receptors were missing in the periphery, perhaps reducing the inflammatory response after stroke. Giffard said that the team did see a reduction in some features of inflammation, but not in others.
The authors also tested knockout brain slices by inducing a test tube version of stroke, depriving the slices of oxygen and glucose. Slices of knockouts had less cell death than control slices, showing that at least part of the effect the team observed was due to a lack of MHC1 molecules in the brain itself, though immune system effects may also play a role.
Stroke is a graveyard of drug discovery empires, and other attempts to target plasticity have not been exempt from the carnage. Pharmacological strategies aimed at a major plasticity receptor in the brain, the NMDA receptor, such as ACEA-1021 (licostinel) and Cerestat (aptiganel), have joined the ranks of failed stroke drugs. (See BioWorld Today, July 14, 1998.)
Those drugs, however, would have had the net effect of decreasing plasticity. Excess activation of the NMDA receptor can be toxic to neurons, and so the NMDA-targeting therapies were trying to block NMDA receptors.
Giffard said one method of increasing plasticity that has had at least partly encouraging results has been old-fashioned rehabilitation, that is, physical therapy to encourage the use of body parts that can't be controlled any more after a stroke. Here, some studies have shown an effect, while others have failed to do so.
She added that one possibility for the discrepancy is the timing of the intervention. Presently, it is not clear whether it is best to start recovery-focused interventions as soon as possible after a stroke, or whether giving the brain a little time off ultimately leads to better results. Working out the optimal timing will be a "key question" for any approach targeting MHC1 molecules or PirB as well. But the fact that the mice continued to make greater gains for at least a week suggested that the window of opportunity to use any such therapy, if it pans out, will be far longer than the three hours of the only approved stroke drug, Genentech Inc.'s clot buster tPA.
Giffard said that it's "hard to extrapolate" from the mouse data exactly how long the time window would be. But from the studies that do show an effect of rehabilitation, one thing is already clear: "Improvements can go on for a very long time."
Outside of the US
In the U.S. and Canada: +1-800-336-4474
Outside the U.S.: +44-203-684-1796
Hours: Monday - Friday, 8:00am - 6:00 pm EST