Running exercise improves spatial learning and memory ability and enhances angiogenesis in the cerebral cortex via endogenous nitric oxide

The molecular mechanisms by which exercise improves brain function and capillaries in the cerebral cortex are unclear. Exercise can increase the expression of nitric oxide (NO) in the brain, and endogenous NO is thought to exert beneficial effects on proangiogenic factors, antiangiogenic factors and brain function. Therefore, we hypothesized that running exercise might improve brain function and enhance angiogenesis through endogenous NO. The following three groups of rats were administered intracerebroventricular (i.c.v.) injections before running exercise each day for 4 weeks: exercise+L-NAME group (i.c.v. L-NAME, an NO synthase blocker, dose: 1 μmol/μl and 5 μl/day; treadmill exercise, 20 min/day), exercise group (i.c.v. normal saline, 5 μl/day; treadmill exercise, 20 min/day), and sham group (i.c.v. normal saline, 5 μl/day; no treadmill exercise). Subsequently, the spatial learning and memory abilities were tested using a Morris water maze, and the nitric oxide synthase (NOS) activity in the cerebral cortex in each group of rats was measured using a method involving nitric acid reductase and metabolic chemistry. The parameters of the cortical capillaries were quantitatively investigated using an immunohistochemistry technique and stereological methods. The expression levels of proangiogenic factors (VEGF and FGF-2) and an antiangiogenic inhibitor (endostatin) in the cerebral cortex were tested using a Western blot analysis. Running exercise significantly improved the rats' spatial learning and memory abilities and increased NOS activity in the cortex. Running exercise also subsequently improved the expression of proangiogenic factors (VEGF and FGF-2) and the length, volume and surface area of capillaries and reduced the expression of antiangiogenic factors (endostatin) in the cortex. In contrast, the L-NAME treatment attenuated the effects of running exercise. Running exercise regulates proangiogenic factors, antiangiogenic factors and angiogenesis in the cerebral cortex via a partially NO-dependent mechanism, and influencing endogenous NO might potentially affect the exercise-related beneficial effects on cognitive ability and cortical capillaries.