Scientists from the University of Leeds and Zhejiang University in China say they have discovered a mechanism linked to the brain damage often suffered by stroke victims. They are now searching for drugs to block it.
Strokes happen when the blood supply to part of the brain is cut off but much of the harm to survivors' memory and other cognitive function is often actually caused by “oxidative stress” in the hours and days after the blood supply resumes. The researchers studied this second phase of damage in laboratory mice and found a mechanism in neurons that, if removed, reduced the damage to brain function.
Co-author Dr Lin-Hua Jiang, of the University of Leeds' School of Biomedical Sciences, said: “Until now, much of the drug research has been focusing on the direct damage caused by the loss of blood flow, but this phase can be hard to target,” said Lin-Hua Jiang, Ph.D., of the University of Leeds’ school of biomedical sciences. “The patient may not even be in the ambulance when it is happening. We have found a mechanism that is linked to the next phase of damage that will often be underway after patients have been admitted to hospital.”
The study (“TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia”) published in Cell Death and Disease, looked at the damage caused by the excessive production of reactive oxygen species in brain tissues immediately after blood supply is re-established. In a healthy brain, there are low levels of reactive oxygen species, but the quantity dramatically increases after a stroke to levels that are harmful to neurons.
According to Dr. Jiang, “We identified an 'ion channel' in the membranes of neurons, called TRPM2, which is switched on in the presence of the reactive oxygen species. [The ion channel serves as a] door in the membrane of a cell that allows it to communicate with the outside world. TRPM2 opens when the harmful levels of reactive oxygen species are present and we found that removing it significantly reduced neuronal cell damage.”
The researchers compared the effects of strokes on mice with TRPM2 with a transgenic strain without it.
“In the mice in which the TRPM2 channel does not function, the reactive oxygen species are still produced but the neurons are very much protected. The neuronal death is significantly reduced. More importantly, we observed a significant difference in brain function, with the protected mice demonstrating significantly superior memory in lab tests,” said Dr Jiang.
“These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn2+]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury,” wrote the investigators.
“This study has pinpointed a very promising drug target. We are now screening a large chemical library to find ways of effectively inhibiting this channel. Our ongoing research using animal models is testing whether blockage of this channel can offer protection again brain damage and cognitive dysfunction in stroke patients,” noted Dr Jiang.