Downregulation of miRNA-134 protects neural cells against ischemic injury in N2A cells and mouse brain with ischemic stroke by targeting HSPA12B

Ischemic stroke is one of the main causes of mortality and disability worldwide. However, efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatment of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis, and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in research on the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under the ischemic condition and cells engraftment for ischemic treatment. Then, we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.

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Urokinase-type plasminogen activator (uPA) protects the tripartite synapse in the ischemic brain via ezrin-mediated formation of peripheral astrocytic processes

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18783653 ◽

2018 ◽

Vol 39 (11) ◽

pp. 2157-2171 ◽

Cited By ~ 5

Author(s):

Ariel Diaz ◽

Paola Merino ◽

Luis G Manrique ◽

Lihong Cheng ◽

Manuel Yepes

Keyword(s):

Ischemic Stroke ◽

Plasminogen Activator ◽

Harmful Effect ◽

Ischemic Injury ◽

Adult Brain ◽

Subsequent Formation ◽

Ischemic Brain ◽

Tripartite Synapse ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator

Cerebral ischemia has a harmful effect on the synapse associated with neurological impairment. The “tripartite synapse” is assembled by the pre- and postsynaptic terminals, embraced by astrocytic elongations known as peripheral astrocytic processes (PAPs). Ischemic stroke induces the detachment of PAPs from the synapse, leading to synaptic dysfunction and neuronal death. Ezrin is a membrane-associated protein, required for the formation of PAPs, that links the cell surface to the actin cytoskeleton. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) promotes neurite growth during development. In the adult brain, neurons release uPA and astrocytes recruit uPAR to the plasma membrane during the recovery phase from an ischemic stroke, and uPA/uPAR binding promotes functional improvement following an ischemic injury. We found that uPA induces the synthesis of ezrin in astrocytes, with the subsequent formation of PAPs that enter in direct contact with the synapse. Furthermore, either the release of neuronal uPA or intravenous treatment with recombinant uPA (ruPA) induces the formation of PAPs in the ischemic brain, and the interaction of these PAPs with the pre- and postsynaptic terminals protects the integrity of the “tripartite synapse” from the harmful effects of the ischemic injury.

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Macrophage Migration Inhibitory Factor Alters Functional Properties of CA1 Hippocampal Neurons in Mouse Brain Slices

International Journal of Molecular Sciences ◽

10.3390/ijms21010276 ◽

2019 ◽

Vol 21 (1) ◽

pp. 276 ◽

Cited By ~ 1

Author(s):

Eric Bancroft ◽

Rahul Srinivasan ◽

Lee A. Shapiro

Keyword(s):

Ischemic Stroke ◽

Mouse Brain ◽

Migration Inhibitory Factor ◽

Hippocampal Neurons ◽

Macrophage Migration Inhibitory Factor ◽

Hippocampal Slices ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Cns Injury ◽

Neuronal Function

Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca2+ events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to N-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus.

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Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/426069 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Juhyun Song ◽

Joohyun Park ◽

Yumi Oh ◽

Jong Eun Lee

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Cerebral Infarction ◽

Infarct Size ◽

Cell Survival ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Cerebral Infarct ◽

Ros Scavenging ◽

The Brain

Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusionin vivoand the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditionsin vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death.

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