Abstract
BackgroundThis study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS).Methods and resultsAdult male SD rats (n = 70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2 × 106 cells/by LICA administration 3 h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS), and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2, and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (all P < 0.0001). By day 60, the endothelial cell markers at protein and cellular levels and number of small vessels exhibited an opposite pattern of BIV among the groups (all P < 0.0001). The protein and cellular levels of inflammation, and protein levels of oxidative stress, autophagy, and apoptosis were highest in group 2, lowest in group 1, and progressively increased from groups 3 to 7 (all P < 0.0001). The angiogenesis biomarkers at protein and cellular levels were significantly progressively increased from groups 1 to 3, then significantly progressively decreased from groups 4 to 7 (all P < 0.0001).ConclusionEarly EPC administration provided better benefits on improving functional/image/molecular-cellular outcomes after acute IS in rat.
Highlights
Divergent etiologies cause stroke, atherosclerotic intracranial arterial stenosis/occlusion remains one of the common causes of ischemic stroke (IS) worldwide [1,2,3,4,5,6] and is associated with a high risk of frequently recurrent IS once IS developed [7,8,9]
The brain infarct volume (BIV) at day 60 after IS and the time courses of corner test after acute IS (Figs. 1 and 2) At day 60 after acute IS, the brain magnetic resonance imaging (MRI) demonstrated that the BIV was lowest in SC, highest in IS, and significantly and progressively increased from EPC3h, EPC3d, EPC7d, EPC14d, to EPC28d (Fig. 1)
At day 3 after acute IS, the neurological function was significantly impaired in all the IS groups regardless with or without treatment than in SC, but it showed no difference among the six IS groups (Fig. 2)
Summary
Divergent etiologies cause stroke, atherosclerotic intracranial arterial stenosis/occlusion remains one of the common causes of ischemic stroke (IS) worldwide [1,2,3,4,5,6] and is associated with a high risk of frequently recurrent IS once IS developed [7,8,9]. The results revealed that this therapy significantly reduced the brain infarct size and improved neurological dysfunction after acute IS in rodent mainly through enhancement of angiogenesis and neurogenesis and reduction of inflammation, oxidative stress, and cellular apoptosis [17] The results of these studies [15,16,17] encouraged us to perform a phase I clinical trial of intracarotid artery transfusion of circulatory-derived autologous EPCs into brain infarct area in old IS stroke patients [18]. This study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS)
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