scholarly journals Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons

2021 ◽  
Vol 22 (24) ◽  
pp. 13442
Author(s):  
Guy C. Brown
Keyword(s):  
Ischemic Stroke ◽  
Neuronal Loss ◽  
Rodent Models ◽  
Brain Areas ◽  
Complement Components ◽  
Behavioral Deficits ◽  
Treatment Targets ◽  
Microglial Phagocytosis

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.

Treatment targets for M2 microglia polarization in ischemic stroke

2018 ◽  
Vol 105 ◽  
pp. 518-525 ◽  
Author(s):  
Ji wang ◽  
Hongyi xing ◽  
Lin wan ◽  
Xingjun jiang ◽  
Chen wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Treatment Targets ◽  
M2 Microglia ◽  
Microglia Polarization

scholarly journals LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

2020 ◽  
Vol 12 (565) ◽  
pp. eaay0399
Author(s):  
Changyoun Kim ◽  
Alexandria Beilina ◽  
Nathan Smith ◽  
Yan Li ◽  
Minhyung Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Activated T Cells ◽  
Behavioral Deficits ◽  
Downstream Signaling ◽  
Toll Like Receptor 2 ◽  
Factor Α

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein–mediated microglial neurotoxicity via lowering of tumor necrosis factor–α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

scholarly journals Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

2020 ◽  
Vol 13 (626) ◽  
pp. eaay5686 ◽  
Author(s):  
Feifei Ma ◽  
Ping Sun ◽  
Xuejing Zhang ◽  
Milton H. Hamblin ◽  
Ke-Jie Yin
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Protein Abundance ◽  
Barrier Dysfunction ◽  
Small Noncoding Rnas ◽  
Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

scholarly journals C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Science ◽  
2015 ◽  
Vol 348 (6239) ◽  
pp. 1151-1154 ◽  
Author(s):  
J. Chew ◽  
T. F. Gendron ◽  
M. Prudencio ◽  
H. Sasaguri ◽  
Y.-J. Zhang ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Behavioral Deficits ◽  
Repeat Expansions

scholarly journals Compromised blood-brain barrier competence in remote brain areas in ischemic stroke rats at the chronic stage

2014 ◽  
Vol 522 (13) ◽  
pp. 3120-3137 ◽  
Author(s):  
Svitlana Garbuzova-Davis ◽  
Edward Haller ◽  
Stephanie N. Williams ◽  
Eithan D. Haim ◽  
Naoki Tajiri ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Areas ◽  
Chronic Stage ◽  
Blood Brain

scholarly journals SMTP-7, a Novel Small-Molecule Thrombolytic for Ischemic Stroke: A Study in Rodents and Primates

2013 ◽  
Vol 34 (2) ◽  
pp. 235-241 ◽  
Author(s):  
Hironobu Sawada ◽  
Naoko Nishimura ◽  
Eriko Suzuki ◽  
Jie Zhuang ◽  
Keiko Hasegawa ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Small Molecule ◽  
Focal Cerebral Ischemia ◽  
Alternative Therapy ◽  
Plasminogen Activation ◽  
Rodent Models ◽  
Promising Candidate ◽  
Mca Occlusion ◽  
Stachybotrys Microspora ◽  
Occlusion Model

SMTP-7 ( Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model ( n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.

scholarly journals Pattern of white matter degeneration in remote brain areas from the basal ganglion lesion of ischemic stroke patients with motor impairment

2020 ◽  
Author(s):  
xuejin cao ◽  
Zan Wang ◽  
Xiaohui Chen ◽  
Yanli Liu ◽  
Xi Yang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Basal Ganglia ◽  
Diffusion Tensor ◽  
Brain Magnetic Resonance Imaging ◽  
Motor Dysfunction ◽  
Stroke Patients ◽  
Brain Areas ◽  
Ischemic Lesion ◽  
Structural Network

Abstract Background Diffusion tensor imaging (DTI) studies have revealed distinct white matter characteristic of brain following diseases. Beyond the lesion-symptom mapping, recent studies have demonstrate extensive structural and functional alterations of remote areas to local lesions caused by stroke in the brain. Here, we investigated the influences further from a global level by multivariate pattern analysis (MVPA) and network-based statistic (NBS). Methods Ten ischemic stroke patients with basal ganglia lesion and motor dysfunction and eleven demographically matched adults underwent brain Magnetic Resonance Imaging scans. DTI data was processed to obtain fractional anisotropy (FA) map and MVPA was used to explore brain regions that play an important role in classification based on FA map. White matter (WM) structural network was constructed by the deterministic fiber tracking approach according to the Automated Anatomical Labeling (AAL) atlas. NBS was used to explore differences of structural network between groups. Results MVPA applied to FA images correctly identified stroke patients with a statistically significant accuracy of 100% (P ≤ 0.001). Compared with the controls, the patients showed an FA reduction in the perilesional basal ganglia and brainstem, with a few in bilateral frontal lobes. Using NBS, we found the significant decreased FA-weighted WM subnetwork in stroke patients. Conclusions We identified some patterns of WM degeneration in the affected brain areas remote from the ischemic lesion, revealed the abnormal topological organization of WM network in stroke patients, which may be helpful for understanding of the neural mechanism of stroke sequela.

scholarly journals P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

2019 ◽  
Author(s):  
Ruoxue Wen ◽  
Hui Shen ◽  
Shuxian Huang ◽  
Liping Wang ◽  
Zongwei Li ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Myosin Light Chain ◽  
Artery Occlusion ◽  
Walking Test ◽  
Microglial Phagocytosis ◽  
Tnf Α ◽  
Severity Scores ◽  
P2y6 Receptor ◽  
Cerebral Artery Occlusion ◽  
The Brain

Abstract Background Clearance of damaged cells is beneficial for the functional recovery after brain injury. Phagocytosis of tissue and cell debris is an important function of microglia during the development and pathological diseases. However, which specific phagocytic receptor mediates microglial phagocytosis after ischemic stroke is obscure. Methods ICR mice (n=59) underwent 90 minutes transient middle cerebral artery occlusion. P2Y6R, Iba1, GFAP and Tuj-1 double immunostainings were performed to determine P2Y6 receptor location. MRS2578 was injected into mice to inhibit P2Y6 receptor activity. Iba1 and TUNEL staining were performed to examine microglia phagocytosis. Modified neurological severity scores and Grid walking test were used to evaluate the neurological function after ischemic stoke. The expression of IL-1 α, IL-1 β, IL-6, IL-10, TNF-α, TGF-β and MPO was used to examine the inflammation response in the brain. Results The expression of P2Y6 receptor in microglia increased within three days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function using modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1β, IL-6, IL-10, TNF-α, TGF-β and MPO after ischemic stroke, which suggested that it had no effect on the inflammation in the brain. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in ischemic mice, which suggested that myosin light chain kinase was involved in P2Y6 receptor mediated phagocytosis. Conclusion Our results indicated that the P2Y6 receptor mediated microglial phagocytosis played an important role during the acute stage of ischemic stroke, which was a potential target for ischemic stroke treatment.

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