The death of neurons in stroke and brain trauma is caused by the malfunctioning of a cell signaling system that normally plays a part in laying down memories, according to a study by researchers at the San Francisco VA Medical Center and the University of California, San Francisco.
For years, it has been known that neuronal death in these conditions is caused in part by the release of superoxide, a highly reactive form of oxygen that is toxic to brain cells. In the current study, a team led by Raymond A. Swanson, MD, chief of neurology and rehabilitation at SFVAMC, has now shown that the primary source of superoxide is the enzyme NADPH oxidase – and not, as scientists have suspected, mitochondria, which power cells.
“This discovery is important, because in NADPH oxidase we now have a therapeutic target,” says Swanson, who is also professor and vice chair of neurology at UCSF. “If we can block NADPH oxidase from producing superoxide, we can potentially prevent neuronal death.”
The finding appears in the Advance Online Publication section of the website of Nature Neuroscience.
Swanson says that when memories are formed, superoxide produced by NADPH oxidase serves as a key signaling molecule between neurons. “Glutamate, a neurotransmitter, stimulates NMDA receptors, which are glutamate receptors in neurons,” he explains. “In turn, NMDA receptors briefly activate NADPH oxidase, which produce superoxide. It’s been shown by other research groups that when you block NADPH oxidase, you block memory formation.”
Now, Swanson and his team have shown that the same system can malfunction when the NMDA receptor is overstimulated, as occurs during stroke. In their experiments, over-stimulation of NMDA receptors leads to generation of toxic amounts of superoxide, resulting in neuronal death.
The researchers demonstrated this connection in two ways. First, they cultured neurons that lacked NADPH oxidase and found that no neurons died when NMDA receptors were overstimulated.
Then, with injections of glutamate or NMDA, they overstimulated NMDA receptors in the brains of mice that lacked NADPH oxidase and again found that no neurons died.
According to Swanson, the experiments exonerate mitochondria, which have been widely suspected as the source of superoxide induced by NMDA receptor activation. “Since mitochondria take oxygen and combine it with glucose to make energy for the cell, there’s good reason to think that this process could go awry – but not, as it turns out, under these conditions,” he says.
One potential application of the research, says Swanson, is during thrombolytic therapy, when drugs are infused into the brain to break up a clot, resulting in reperfusion, or resumption of blood flow: “Under those conditions, physicians know that the superoxide production occurs at the time of reperfusion into the brain, and this would be an ideal setting in which to administer an NADPH oxidase inhibitor,” thus potentially preventing neuronal death.
He notes that while there are several compounds known to inhibit NADPH oxidase, but none are FDA approved for human use at present. “This work adds more impetus for bringing them to the fore,” he says.
Swanson cautions that several of the steps between NMDA receptor activation and NADPH oxidase activation remain unclear. “We know some pieces of the pathway,” he says. “But it will be important to understand the whole system.”
Co-authors of the study are Angela M. Brennan, PhD, Sang Won Suh, PhD, Seok Joon Won, PhD, Tiina M. Kauppinen, PhD, Hokyou Lee, BS, and Ylva Edling, PhD, of SFVAMC and UCSF, and Pak H. Chan, PhD, and Purnima Narasimhan, PhD, of Stanford University.
The research was supported by funds from the Department of Veterans Affairs and the National Institutes of Health, some of which were administered by the Northern California Institute for Research and Education.
NCIRE - the Veterans Health Research Institute - is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.
SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.