Long-Term Exercise Improves Memory Deficits via Restoration of Myelin and Microvessel Damage, and Enhancement of Neurogenesis in the Aged Gerbil Hippocampus After Ischemic Stroke

Ahn, Ji Hyeon; Choi, Jung Hoon; Park, Joon Ha; Kim, In Hye; Cho, Jeong Hwi; Lee, Jae Chul; Koo, Hyun Mo; Hwangbo, Gak; Yoo, Ki‐Yeon; Lee, Choong Hyun; Hwang, In Koo; Cho, Jun Hwi; Choi, Soo Young; Kwon, Young Guen; Kim, Young Myeong; Kang, Il Jun; Won, Moo Ho

doi:10.1177/1545968316638444

Cited by 52 publications

(35 citation statements)

References 61 publications

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“…Notably, we found that BBB integrity in I/R injury was also preserved by Sac-1004-induced stabilization of tight junction proteins and SMI-71 and GLUT-1. A decreased and dysregulated expression pattern of these proteins can be highly susceptible to brain damage during ischemic events [61–63]. The Sac-1004-mediated restoration of these proteins can be an important step to preserve an intact brain region from ischemic damage.…”

Section: Discussionmentioning

confidence: 99%

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

Zhang

Park

Maharjan

et al. 2017

J Neuroinflammation

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BackgroundBlood–brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring.ResultsHere, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-κB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation.ConclusionsTaken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0897-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

Zhang

Park

Maharjan

et al. 2017

J Neuroinflammation

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“…Following the method described in our previous study (20), the gerbils were anesthetized with a mixture of 2.5% isoflurane (Baxter Healthcare Corporation, Deerfield, IL, USA) in 33% oxygen and 67% nitrous oxide. After a sagittal ventral midline incision, common carotid arteries were carefully separated from the respective vagal nerves and were occluded for 5 min using nontraumatic aneurysm clips (Yasargil FE 723K; Aesculap AG, Tuttlingen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Tissue processing was performed according to a previously published procedure (20). Briefly, animals (n=7/group) were anesthetized with sodium pentobarbital (40 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

Effects of long-term post-ischemic treadmill exercise on gliosis in the aged gerbil hippocampus induced by transient cerebral ischemia

Ahn

Shin

Park

et al. 2017

Molecular Medicine Reports

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Therapeutic exercise is an integral component of the rehabilitation of patients who have suffered a stroke. The objective of the present study was to use immunohistochemistry to investigate the effects of post-ischemic exercise on neuronal damage or death and gliosis in the aged gerbil hippocampus following transient cerebral ischemia. Aged gerbils (male; age, 22–24 months) underwent ischemia and were subjected to treadmill exercise for 1 or 4 weeks. Neuronal death was detected in the stratum pyramidale of the hippocampal CA1 region and in the polymorphic layer of the dentate gyrus using cresyl violet and Fluoro-Jade B histofluorescence staining. No significant difference in neuronal death was identified following 1 or 4 weeks of post-ischemic treadmill exercise. However, post-ischemic treadmill exercise affected gliosis (the activation of astrocytes and microglia). Glial fibrillary acidic protein-immunoreactive astrocytes and ionized calcium binding adaptor molecule 1-immunoreactive microglia were activated in the CA1 and polymorphic layer of the dentate gyrus of the group without treadmill exercise. Conversely, 4 weeks of treadmill exercise significantly alleviated ischemia-induced astrocyte and microglial activation; however, 1 week of treadmill exercise did not alleviate gliosis. These findings suggest that long-term post-ischemic treadmill exercise following transient cerebral ischemia does not influence neuronal protection; however, it may effectively alleviate transient cerebral ischemia-induced astrocyte and microglial activation in the aged hippocampus.

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“…Treadmill exercise promotes oligodendrocytes and, thus, myelination. In addition, the improvement of ischemia-induced myelin injury by long-term exercise is related to increased BdNF expression (28). Although the authors' previous studies (25,29,30) have focused on the neuroprotective effect of treadmill exercise in adult rats its neuroprotective effect on juvenile rats has not been explored.…”

Section: Treadmill Exercise Promotes Neurogenesis and Myelin Repair Vmentioning

confidence: 99%

Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β‑catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion

et al. 2020

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Physical exercise has a neuroprotective effect and is an important treatment after ischemic stroke. Promoting neurogenesis and myelin repair in the penumbra is an important method for the treatment of ischemic stroke. However, the role and potential mechanism of exercise in neurogenesis and myelin repair still needs to be clarified. The goal of the present study was to ascertain the possible effect of treadmill training on the neuroprotective signaling pathway in juvenile rats after ischemic stroke. The model of middle cerebral artery occlusion (McAO) in juvenile rats was established and then the rats were randomly divided into 9 groups. XAV939 (an inhibitor of the Wnt/β-catenin pathway) was used to confirm the effects of the Wnt/β-catenin signaling pathway on exercise-mediated neurogenesis and myelin repair. Neurological deficits were detected by modified neurological severity score, the injury of brain tissue and the morphology of neurons was detected by hematoxylin-eosin staining and Nissl staining, and the infarct volume was detected by 2,3,5-triphenyl tetrazolium chloride staining. The changes in myelin were observed by Luxol fast blue staining. The neuron ultrastructure was observed by transmission electron microscopy. Immunofluorescence and western blots analyzed the molecular mechanisms. The results showed that treadmill exercise improved neurogenesis, enhanced myelin repair, promoted neurological function recovery and reduced infarct volume. These were the results of the upregulation of Wnt3a and nucleus β-catenin, brain-derived neurotrophic factor (BdNF) and myelin basic protein (MBP). In addition, XAV939 inhibited treadmill exercise-induced neurogenesis and myelin repair, which was consistent with the downregulation of Wnt3a, nucleus β-catenin, BdNF and MBP expression, and the deterioration of neurological function. In summary, treadmill exercise promotes neurogenesis and myelin repair by upregulating the Wnt/β-catenin signaling pathway, to improve the neurological deficit caused by focal cerebral ischemia/reperfusion.

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Long-Term Exercise Improves Memory Deficits via Restoration of Myelin and Microvessel Damage, and Enhancement of Neurogenesis in the Aged Gerbil Hippocampus After Ischemic Stroke

Abstract: These results suggest that long-term treadmill exercise after I-R can restore memory function through replacement of multiple damaged structures in the ischemic aged hippocampus.

Cited by 52 publications

References 61 publications

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia—reperfusion injury by suppressing blood–brain barrier disruption and inflammation

Effects of long-term post-ischemic treadmill exercise on gliosis in the aged gerbil hippocampus induced by transient cerebral ischemia

Treadmill exercise promotes neurogenesis and myelin repair via upregulating Wnt/β‑catenin signaling pathways in the juvenile brain following focal cerebral ischemia/reperfusion

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