A mystery of basic cell metabolism that has persisted for a century has come a major step closer to giving up its secrets.
University scientists have identified a mechanism that triggers increased blood flow to brain cells actively engaged in work.
The findings appear in two papers in the Jan. 13 issue of the Proceedings of the National Academy of Sciences (PNAS).
The researchers hope to apply the new insights to improve understanding of basic brain function and limit side effects of diabetes, but the results could also have much wider ramifications.
“One can pick out any number of diseases in which knowing how increased blood flow in the brain is activated, will be very important and useful,” said Marcus E. Raichle, M.D., professor of radiology, of neurology and of anatomy and neurobiology. “Changes in circulation of blood in the brain are linked, for example, to Alzheimer’s disease and stroke.”
Scientists have known since the late 1800s that when a muscle cell contracts repeatedly or a nerve cell increases its activity, the circulatory system responds by increasing blood flow to the activated cells. They assumed this happens so the blood can supply the cells with more sugar and oxygen, fueling their ability to increase their workload.
Over the past decade, a growing body of evidence has suggested that this idea, logical as it seems, is incorrect. The new University studies (one conducted in animals and the other in humans) give scientists a sense for how blood flow increases. Why it increases is still elusive, but knowing how the increase is triggered will provide vital aid to answering that question.
Raichle, who led the PNAS human study, also directed a 1988 study that found increased brain activity increased blood flow much more than brain cells’ consumption of oxygen.
Later University studies confirmed the surprising finding that the reason for increased blood flow wasn’t to bring in additional sugar or oxygen.
Joseph Williamson, M.D., a retired University pathologist, read Raichle’s 1988 study and was intrigued. Williamson, the lead investigator for the other University study appearing in PNAS, specializes in the effects of diabetes.
In addition to elevating sugar levels throughout the body, diabetes also increases blood flow and can cause damage to nerves, retinas and kidneys.
Williamson was struck by a similarity between working muscle cells and cells of diabetic patients in regions likely to be damaged by the disease: Both experienced increases in the ratio of two forms of a key energy-producing compound, nicotinamide adenine dinucleotide (NAD).
“Because of its role as the major carrier of electrons and protons from fuels for energy metabolism, NAD is strategically positioned to coordinate blood flow with energy metabolism,” Williamson said.
When in use as a carrier of electrons and protons, NAD is converted to NADH (NAD plus H, or one atom of hydrogen). Williamson thought the ratio between these two forms of the compound NADH/NAD might be modulating blood flow.
Two other compounds involved in energy production, pyruvate and lactate, can affect cells’ ratio of NADH to NAD.
Williamson decided to try using this connection to test his theory. With University colleagues in 2001, he showed in rats that blood flow to working skeletal muscle increased even more than normal after lactate injections, which increase the NADH/NAD ratio. Injections of pyruvate, which decrease the ratio, had the opposite effect.
In the new paper, the same effects were detected in the rat retina and visual region of the brain during optical stimulation.
For the human research, seven subjects were studied using PET imaging scans. Participants were asked either to close their eyes during the scans or to fix their gaze on an unmoving central crosshair in an animated visual display.
Mark Mintun, M.D., professor of radiology and of psychiatry, was lead author of the human study. Mintun, Raichle and their colleagues have a follow-up human study using pyruvate injections under way.
Williamson is using the results of the studies to build his case for a new understanding of how diabetes causes damage to tissues. He believes the same signaling pathways activated by increased NADH/NAD ratios may also trigger the production of chemically reactive compounds that damage cells.