Abstract
Trillium tschonoskii Maxim. (TTM), is a perennial herb from Liliaceae, that has been widely used as a traditional Chinese medicine treating cephalgia and traumatic hemorrhage. The present work was designed to investigate whether the total saponins from Trillium tschonoskii Maxim. (TSTT) would promote brain remodeling and improve gait impairment in the chronic phase of ischemic stroke. A focal ischemic model of male Sprague-Dawley (SD) rats was established by permanent middle cerebral artery occlusion (MCAO). Six hours later, rats were intragastrically treated with TSTT (120, 60, and 30 mg/kg) and once daily up to day 30. The gait changes were assessed by the CatWalk-automated gait analysis system. The brain tissues injuries, cerebral perfusion and changes of axonal microstructures were detected by multimodal magnetic resonance imaging (MRI), followed by histological examinations. The axonal regeneration related signaling pathways including phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3)/collapsin response mediator protein-2 (CRMP-2) were measured by western blotting. TSTT treatment significantly improved gait impairment of rats. MRI analysis revealed that TSTT alleviated tissues injuries, significantly improved cerebral blood flow (CBF), enhanced microstructural integrity of axon and myelin sheath in the ipsilesional sensorimotor cortex and internal capsule. In parallel to MRI findings, TSTT preserved myelinated axons and promoted oligodendrogenesis. Specifically, TSTT interventions markedly up-regulated expression of phosphorylated GSK-3, accompanied by increased expression of phosphorylated PI3K, AKT, but reduced phosphorylated CRMP-2 expression. Taken together, our results suggested that TSTT facilitated brain remodeling. This correlated with improving CBF, encouraging reorganization of axonal microstructure, promoting oligodendrogenesis and activating PI3K/AKT/GSK-3/CRMP-2 signaling, thereby improving poststroke gait impairments.
Highlights
Cerebral ischemia remains to be the most common cause of longterm disability worldwide (Zhou et al, 2021)
We further purified the n-butyl alcohol extract of Trillium tschonoskii Maxim (TTM) by AB-8 macroporous resin, and used noninvasive magnetic resonance imaging (MRI) methodologies to investigate the possible efficacy of re-purified total saponins from Trillium tschonoskii Maxim. (TSTT) on the cerebral blood flow (CBF) recovery and brain tissue modifications in a rat model of focal cerebral ischemia
Compared with middle cerebral artery occlusion (MCAO) group, the expressions of p-GSK-3α/β were markedly upregulated by TSTT (120, 60, and 30 mg/kg) treatments (p < 0.01 or p < 0.05, Figure 8E). These results suggested that TSTT effectively prevented glycogen synthase kinase-3 (GSK-3) activation after ischemic stroke
Summary
Cerebral ischemia remains to be the most common cause of longterm disability worldwide (Zhou et al, 2021). We found that the n-butyl alcohol extract of TTM significantly decreased brain injuries and improved neurobehavioral function of ischemic rats during the subacute phase of stroke (poststroke day 15) (Li M. et al, 2018), suggesting the total saponins of Trillium tschonoskii Maxim (TSTT) may have the potential neuroprotective and repair potentiality. Whether the TSTT leads to long-term functional recovery and brain remodeling in the chronic phase of ischemic stroke is unknown To address this gap, we further purified the n-butyl alcohol extract of TTM by AB-8 macroporous resin, and used noninvasive MRI methodologies to investigate the possible efficacy of re-purified TSTT on the cerebral blood flow (CBF) recovery and brain tissue modifications in a rat model of focal cerebral ischemia. We further explored the axonal growth pathway (PI3K/AKT/ GSK-3/CRMP-2) to gain an insight into the possible repair mechanisms underlying TSTT treatment following ischemic stroke
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