The three-phase enriched environment paradigm promotes neurovascular restorative and prevents learning impairment after ischemic stroke in rats

Zhan, Yuan; Li, Man-Zhong; Yang, Le; Feng, Xuefeng; Lei, Jianfeng; Zhang, Nan; Zhao, Yuanyuan; Zhao, Hui

doi:10.1016/j.nbd.2020.105091

Cited by 36 publications

(57 citation statements)

References 77 publications

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“…Rats subject to intracerebral hemorrhage show functional improvement and an increase in the survival of neurons [ 209 ]. A three-phase paradigm for EE where the EE for rats was changed based on the three phases of stroke revealed changes to the ischemic microenvironment including significantly improved survival of cortical and striatal neurons, improved cerebral blood flow, decreased BBB damage, and increased angiogenesis via modified VEGF, Angiopoietin-1 and Angiopoietin-2 compared to standard housing rats [ 210 ]. EE provides an animal model for rehabilitation measurable through standardized behavioral assessments not common in traditional human rehabilitation due to the lack of standardization and subjectivity of clinician experience [ 203 ].…”

Section: Remodeling Of Stroke Tissue Microenvironment Outside the Brainmentioning

confidence: 99%

“…Additionally, EE alone also positively affected neurovascular remodeling and revascularization through VEGF. MSCs increased vascular remodeling through VEGF and proves that EE has an additive effect through more than just neurogenesis and synaptic plasticity, but in modulating the microenvironment and maintaining homeostasis as well [ 210 ].…”

Section: Remodeling Of Stroke Tissue Microenvironment Outside the Brainmentioning

confidence: 99%

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Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

et al. 2021

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Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke.

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Section: Remodeling Of Stroke Tissue Microenvironment Outside the Brainmentioning

confidence: 99%

Section: Remodeling Of Stroke Tissue Microenvironment Outside the Brainmentioning

confidence: 99%

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

et al. 2021

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“…In the case of an EE as a rehabilitation model, the modality of the paradigm is also crucial. Indeed, it has been shown that a threephase intervention strategy, wherein the EE cage was periodically rearranged according to three post-stroke phases, promoted long-term neurogenesis, angiogenesis, neurovascular remodeling, spatial learning, and memory in pMCAO rats [43].…”

Section: Combined Cell Therapy and Enriched Environmentmentioning

confidence: 99%

Additive Behavioral Improvement after Combined Cell Therapy and Rehabilitation Despite Long-Term Microglia Presence in Stroke Rats

Bakreen

Juntunen

Dunlop

et al. 2021

IJMS

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Microglia are involved in the post-stroke immunomodulation of brain plasticity, repair, and reorganization. Here, we evaluated whether adipose-tissue-derived mesenchymal stem cells (ADMSCs) and/or rehabilitation improve behavioral recovery by modulating long-term perilesional inflammation and creating a recovery-permissive environment in a rat model of ischemic stroke. Methods: A two-way mixed lymphocyte reaction was used to assess the immunomodulatory capacity of ADMSCs in vitro. Two or 7 days after permanent middle cerebral artery occlusion (pMCAO), rats were intravenously administered ADMSCs or vehicle and housed in a standard or enriched environment (EE). Behavioral performance was assessed with a cylinder test, then we performed stereological and ImageJ/Fiji quantifications of ionized calcium-binding adaptor molecule 1 (Iba1) cells and blood–brain barrier (BBB) leakage. Results: Human ADMSCs were immunosuppressive in vitro. The cylinder test showed partial spontaneous behavioral recovery of pMCAO rats, which was further improved by combined ADMSCs and housing in EE on days 21 and 42 (p < 0.05). We detected an ischemia-induced increase in numbers, staining intensity, and branch length of Iba1+ microglia/macrophages as well as BBB leakage in the perilesional cortex. However, these were not different among pMCAO groups. Conclusion: Combined cell therapy and rehabilitation additively improved behavioral outcome despite long-term perilesional microglia presence in stroke rats.

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“…Meanwhile, exposure to EE enhanced the experience-dependent plasticity of the brain and promoted the recovery of cognitive and motor functions after ischemia/reperfusion (I/R) injury ( Livingston-Thomas et al, 2016 ). EE improved cognitive function via neurogenesis and angiogenesis by regulating the activation of PI3K/AKT/GSK-3/β-catenin signaling pathways and intrinsic axon guidance molecules following I/R ( Zhan et al, 2020 ). Moreover, EE mediated neurogenesis by inhibiting the production and secretion of IL-17A from astrocyte via NF-κB/p65 after I/R injury ( Zhang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury

Liu

Zheng

Yang

et al. 2021

Front. Aging Neurosci.

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Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1β and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1β and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.

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The three-phase enriched environment paradigm promotes neurovascular restorative and prevents learning impairment after ischemic stroke in rats

Cited by 36 publications

References 77 publications

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

Additive Behavioral Improvement after Combined Cell Therapy and Rehabilitation Despite Long-Term Microglia Presence in Stroke Rats

Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury

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