Abstract
Chronic cerebral hypoperfusion (CCH) is identified as a critical risk factor of dementia in patients with cerebrovascular disease. Xiaoshuan enteric-coated capsule (XSECC) is a compound Chinese medicine approved by Chinese State Food and Drug Administration for promoting brain remodeling and plasticity after stroke. The present study aimed to explore the potential of XSECC to improve cognitive function after CCH and further investigate the underlying mechanisms. CCH was induced by bilateral common carotid artery occlusion (BCCAO) in rats. XSECC (420 or 140 mg/kg) treatment remarkably reversed BCCAO-induced cognitive deficits. Notably, after XSECC treatment, magnetic resonance angiography combined with arterial spin labeling noninvasively demonstrated significantly improved hippocampal hemodynamics, and 18F-FDG PET/CT showed enhanced hippocampal glucose metabolism. In addition, XSECC treatment markedly alleviated neuropathologies and improved neuroplasticity in the hippocampus. More importantly, XSECC treatment facilitated axonal remodeling by regulating the phosphorylation of axonal growth related proteins including protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) and collapsin response mediator protein-2 (CRMP2) in the hippocampus. Taken together, the present study demonstrated the beneficial role of XSECC in alleviating BCCAO-induced cognitive deficits by enhancing hippocampal glucose metabolism, hemodynamics and neuroplasticity, suggesting that XSECC could be a useful strategy in cerebral hypoperfusion state and dementia.
Highlights
Vascular cognitive impairment (VCI), which encompasses a large range of cognitive deficits including vascular dementia, has emerged as the second common cause of age-related cognitive impairment[1]
As hippocampus played a central role in cognitive functions, we investigated the possible efficacy of Xiaoshuan enteric-coated capsule (XSECC) on cognitive functions, cerebral hemodynamics, and glucose metabolism, as well as histopathological changes in the hippocampus after bilateral common carotid artery occlusion (BCCAO) and explored the underlying mechanisms
Post hoc analysis showed that BCCAO rats without treatment took more time and covered longer swim paths to find the hidden platform on the 2nd, 3rd, and 4th day as compared with the sham operated controls, indicating the learning capacity was impaired after BCCAO (P < 0.01, Fig. 1a,b)
Summary
XSECC improved the spatial learning and memory in BCCAO rats. Morris water maze test was performed to evaluate the hippocampus-related spatial learning and memory capacity of all rats. Correlative analysis showed that the increased glucose metabolism in the hippocampus was positively correlated with the cognitive performance, suggesting an important role of glucose metabolic abnormality in cognitive impairment induced by CCH These results indicated that XSECC promoted the glucose metabolism following CCH, which might partially contribute to its cognition-improving properties. XSECC treatment markedly attenuated CCH-induced increase in the level of phospho-CRMP2, but increased the expression of phosphorylated AKT and GSK-3β, indicating that XSECC had ability to activate AKT signaling pathway, which might, at least partially, contribute to the effect of promoting neurite outgrowth of XSECC following CCH. The present study suggested that the protective effects of XSECC on CCH-induced cognitive impairment in rats were achieved likely via regulating AKT/GSK-3β/CRMP2 signal pathway, we did not exclude the possibility that other cellular and molecular mechanisms were implicated in XSECC-induced improvement of the cognitive function following CCH. Further investigation as to how XSECC impacts the cell-signaling molecules in the amelioration of vascular cognition disturbance is warranted, which may produce clinical benefits such as protection against CCH-induced neurodegeneration and cognitive deficits
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