Bi-directional network remodeling by reactive astrocytes

AbstractNecroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar. Graphical Abstract

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Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22094333 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4333

Author(s):

Yutaka Koyama

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurotrophic Factors ◽

Drug Target ◽

Therapeutic Strategy ◽

Reactive Astrocytes ◽

Brain Disorders ◽

Etb Receptor ◽

Target Molecules ◽

Endothelin B

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

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Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury

Molecular Neurodegeneration ◽

10.1186/s13024-016-0081-8 ◽

2016 ◽

Vol 11 (1) ◽

Cited By ~ 64

Author(s):

Hong Fan ◽

Kun Zhang ◽

Lequn Shan ◽

Fang Kuang ◽

Kun Chen ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Reactive Astrocytes ◽

Cord Injury

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THE FINE STRUCTURE OF ASTROCYTES IN THE CEREBRAL CORTEX AND THEIR RESPONSE TO FOCAL INJURY PRODUCED BY HEAVY IONIZING PARTICLES

The Journal of Cell Biology ◽

10.1083/jcb.25.2.141 ◽

1965 ◽

Vol 25 (2) ◽

pp. 141-157 ◽

Cited By ~ 183

Author(s):

David S. Maxwell ◽

Lawrence Kruger

Keyword(s):

Cerebral Cortex ◽

Fine Structure ◽

Electron Microscope ◽

Reactive Astrocytes ◽

Lipid Bodies ◽

Particle Irradiation ◽

Fibrous Astrocytes ◽

Primitive Forms ◽

Focal Injury ◽

Glycogen Particles

Normal and reactive astrocytes in the cerebral cortex of the rat have been studied with the electron microscope following focal alpha particle irradiation. The presence of glycogen and approximately 60-A fibrils identify astrocyte cytoplasm in formalin-perfused tissue. The glycogen particles facilitate the identification of small processes and subpial and perivascular end-feet. Both protoplasmic and fibrous astrocytes contain cytoplasmic fibrils and should be distinguished on the basis of the configuration of their processes and their distribution. Acutely reactive astrocytes are characterized by a marked increase in the number of glycogen granules and mitochondria from the first day after irradiation. These cells later hypertrophy and accumulate lipid bodies and increased numbers of cytoplasmic fibrils. The glial "scar" consists of a greatly expanded volume of astrocyte cytoplasm filled with fibrils and displays no signs of astrocyte death, reversion to primitive forms, or extensive multiplication.

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Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

NeuroImmunoModulation ◽

10.1159/000513678 ◽

2021 ◽

pp. 1-8

Author(s):

Ren-Wei Du ◽

Wen-Guang Bu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Underlying Mechanism ◽

Reactive Astrocytes ◽

Dopamine Neurons ◽

Neuron Death ◽

Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

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