Regular physical activity is associated with a decrease of cerebrovascular and cardiovascular events, which may relate to enhanced endothelium-dependent vasodilation. Here, we provide evidence that physical activity protects against ischemic stroke via mechanisms related to the upregulation of endothelial nitric oxide synthase (eNOS) in the vasculature. Voluntary training on running wheels or exercise on a treadmill apparatus for 3 weeks, respectively, reduced cerebral infarct size and functional deficits, improved endothelium-dependent vasorelaxation, and augmented cerebral blood flow in wild-type mice. The neuroprotective effects of physical training were completely absent in eNOS-deficient mice, indicating that the enhanced eNOS activity by physical training was the predominant mechanism by which this modality protects against cerebral injury. Our results suggest that physical activity not only decreases stroke risk, but also provides a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.

Abstract-Physical activity upregulates endothelial nitric oxide synthase (eNOS), improves endothelium function, and protects from vascular disease. Here, we tested whether voluntary running would enhance neovascularization and long-term recovery following mild brain ischemia. Wild-type mice were exposed to 30 minutes of middle-cerebral artery occlusion (MCAo) and reperfusion. Continuous voluntary running on wheels conferred long-term upregulation of eNOS in the vasculature and of endothelial progenitor cells (EPCs) in the spleen and bone marrow (BM). This was associated with higher numbers of circulating EPCs in the blood and enhanced neovascularization. Moreover, engraftment of TIE2/LacZ-positive BM-derived cells was increased in the ischemic brain. Four weeks after the insult, trained animals showed higher numbers of newly generated cells in vascular sites, increased density of perfused microvessels and sustained augmentation of cerebral blood flow within the ischemic striatum. Moreover, running conferred tissue sparing and improved functional outcome at 4 weeks. The protective effects of running on angiogenesis and outcome were completely abolished when animals were treated with a NOS inhibitor or the antiangiogenic compound endostatin after brain ischemia, and in animals lacking eNOS expression. Voluntary physical activity improves long-term stroke outcome by eNOS-dependent mechanisms related to improved angiogenesis and cerebral blood flow.

Previous investigations have established a strong correlation between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU). In the present study the relationship between density of perfused brain capillaries and LCBF or LCGU was investigated in conscious and anesthetized rats. Perfused capillaries were stained by labeling the plasma with the gamma globulin-coupled fluorochromes, fluorescein isothiocyanate (FITC) and lissamine-rhodamine B 200 (RB 200). The density of perfused capillaries was determined in 12 different brain structures by fluorescence microscopy of embedded brain sections following coronal sectioning in a cryostat. Significant differences were found among brain structures investigated; the lowest density of perfused capillaries was found in the white matter (e.g., corpus callosum 162 fragments/mm2), whereas the highest values were determined in the structures of the auditory system (e.g., inferior colliculus 810 fragments/mm2). LCBF and LCGU were measured in two separate groups of rats using standard autoradiographic methods. In all three experimental groups, the same structures were identified and measured with a high degree of accuracy and local resolution. Density of perfused capillaries correlated well with LCBF (r = 0.93) and even better with LCGU (r = 0.97). In addition to the relationship between LCGU and LCBF established by earlier studies, these data show the intimate interrelationship between LCGU, density of perfused capillaries, and LCBF.

The purpose of the present study was to investigate whether or not cerebral glucose utilization is changed locally after damage of the neuronal insulin receptor by means of intracerebroventricular (icv) streptozotocin (STZ) administered in a subdiabetogenic dosage (1.5 mg/kg bw.). STZ was administered at the start of the study, and 2 and 21 days later bilaterally into the cerebral ventricles in rats of a mean age of 18 months. The local distribution of cerebral glucose utilization was analyzed in conscious rats on the 42nd day after the first STZ injection using the quantitative (14C)-2-deoxyglucose method. Of the 35 brain structures investigated from autoradiograms of brain sections, 17 showed a reduction in glucose utilization. Decreases in glucose utilization were observed in the frontal, parietal, sensory motor, auditory and entorhinal cortex and in all hippocampal subfields. In contrast, glucose utilization was increased in two white matter structures. The decrease in cerebral glucose utilization observed in cortical and hippocampal areas in the present study may correspond to changes in morphobiological parameters which have been found in patients with Alzheimer's disease. The present data are in accordance with the hypothesis that an impairment in the control of neuronal glucose metabolism at the insulin receptor site may exist in sporadic dementia of Alzheimer type (DAT), and can be studied by the icv STZ animal model.

The interorgan relationships for glutamine were investigated in normal, chronically acidotic, and diabetic ketoacidotic rats. In the normal rat, muscle tissue is the major site that releases glutamine into the circulation, and the nonhepatic splanchnic bed (mainly gut) is the major site of glutamine uptake. The liver of normal, postabsorptive rats takes up glutamine also. The kidneys have no significant affect on circulating glutamine in normal rats. In chronic NH4Cl and HCl acidosis, muscle glutamine release doubles. In addition, the liver decreases glutamine uptake and releases glutamine into the circulation. Muscle and liver supply, respectively, about 55 and 45% of the increased glutamine demand of the kidneys during chronic acidosis. No significant changes could be detected in the nonhepatic splanchnic bed during acidosis. In diabetic ketoacidotic rats, the increased demand for glutamine by the kidneys is almost entirely supplied by muscle. No significant changes occur in liver or nonhepatic splanchnic bed.