Abstract
Cognitive impairment is closely associated with the slowing of glucose metabolism in the brain. Glucose transport, a rate-limiting step of glucose metabolism, plays a key role in this phenomenon. Previous studies have reported that limb remote ischemic conditioning (LRIC) improves cognitive performance in rats with chronic cerebral hypoperfusion (CCH). Here, we determined whether LRIC could ameliorate cognitive impairment in rats with CCH by regulating glucose transport. A total of 170 male Sprague-Dawley rats were used. Animals subjected to permanent double carotid artery occlusion (2VO) were assigned to the control or LRIC treatment group. LRIC was applied beginning 3 days after the 2VO surgery. We found that LRIC can improve learning and memory; decrease the ratio of ADP/ATP; increase glucose content; upregulate the expression of pAMPKα, GLUT1 and GLUT3; and increase the number of GLUT1 and GLUT3 transporters in cerebral cortical neurons. The expression of GLUT1 and GLUT3 in the cortex displayed a strong correlation with learning and memory. Pearson correlation analysis showed that the levels of GLUT1 and GLUT3 are correlated with neurological function scores. All of these beneficial effects of LRIC were ablated by application of the AMPK inhibitor, dorsomorphin. In summary, LRIC ameliorated cognitive impairment in rats with CCH by regulating glucose transport via the AMPK/GLUT signaling pathway. We conclude that AMPK-mediated glucose transport plays a key role in LRIC. These data also suggest that supplemental activation of glucose transport after CCH may provide a clinically applicable intervention for improving cognitive impairment.
Highlights
Cognitive impairment is closely associated with the slowing of glucose metabolism in the brain
The Morris water maze test on day 6 showed that the percentage of time spent in the target quadrant by the 2VO group was significantly lower than that of rats in the sham group (P
After 4 weeks of LRIC treatment, the content of GLUT1 and GLUT3 in the cortex were negatively correlated with latency time (Figure 6C and D) and positively correlated with the percentage of time spent in the target quadrant during the Morris Water Maze test (Fig. 6E and F). These results suggest that upregulation of GLUT1/GLUT3 may be an important component of LRIC-induced cognitive improvement in the context of chronic cerebral hypoperfusion (CCH)
Summary
Cognitive impairment is closely associated with the slowing of glucose metabolism in the brain. Beyond standard measures to control vascular risk factors such as hypertension and diabetes, only a small number of cholinesterase inhibitors have been clinically proven to be effective and even these only have modest improvement in cognitive function while failing to modify overall prognosis [4] In this setting, there is an urgent need to discover and perfect new therapies designed to prevent the onset of VaD, ameliorate its progression, or both. Adenosine monophosphate activated protein kinase (AMPK) is involved in this process as a molecular center for the control of cell energy metabolism It is found widely distributed in brain tissues and is responsible for controlling the level of energy metabolism in cells by regulating the expression of GLUT genes [27] and its accumulation was found to be associated with a protective effect conferred by remote ischemic conditioning against cerebral hemorrhage [28]
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