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Michinaga, S.; Hishinuma, S.; Koyama, Y. Pathophysiological Responses of Astrocytes to Traumatic Brain Injury. Encyclopedia. Available online: https://encyclopedia.pub/entry/41921 (accessed on 19 July 2025).
Michinaga S, Hishinuma S, Koyama Y. Pathophysiological Responses of Astrocytes to Traumatic Brain Injury. Encyclopedia. Available at: https://encyclopedia.pub/entry/41921. Accessed July 19, 2025.
Michinaga, Shotaro, Shigeru Hishinuma, Yutaka Koyama. "Pathophysiological Responses of Astrocytes to Traumatic Brain Injury" Encyclopedia, https://encyclopedia.pub/entry/41921 (accessed July 19, 2025).
Michinaga, S., Hishinuma, S., & Koyama, Y. (2023, March 07). Pathophysiological Responses of Astrocytes to Traumatic Brain Injury. In Encyclopedia. https://encyclopedia.pub/entry/41921
Michinaga, Shotaro, et al. "Pathophysiological Responses of Astrocytes to Traumatic Brain Injury." Encyclopedia. Web. 07 March, 2023.
Pathophysiological Responses of Astrocytes to Traumatic Brain Injury
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This entry is adapted from the peer-reviewed paper 10.3390/cells12050719

Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ETA receptor (ETA-R) and ETB receptor (ETB-R). ETB-R is highly expressed in reactive astrocytes and upregulated by TBI. Activation of astrocytic ETB-R promotes conversion to reactive astrocytes and the production of astrocyte-derived bioactive factors, including vascular permeability regulators and cytokines, which cause blood–brain barrier (BBB) disruption, brain edema, and neuroinflammation in the acute phase of TBI. ETB-R antagonists alleviate BBB disruption and brain edema in animal models of TBI. The activation of astrocytic ETB receptors also enhances the production of various neurotrophic factors. These astrocyte-derived neurotrophic factors promote the repair of the damaged nervous system in the recovery phase of patients with TBI. 

astrocyte traumatic brain injury endothelin

1. Introduction

Traumatic brain injury (TBI) is critical damage to the brain caused by a sudden insult, such as traffic accidents, falls, collisions, and sporting activities. TBI is a major cause of death and disability worldwide. Even in surviving patients, TBI causes severe sequelae in motor, sensory, mental, and cognitive functions, resulting in decreased quality of life (QOL). Therefore, much effort has been devoted to realizing effective therapies for TBI, that is, treatments to protect the brain from damage in the acute phase and promote the recovery of neurological function in TBI patients with sequelae.
Brain damage caused by TBI is classified as primary or secondary [1][2]. Primary damage includes direct physical injury to the brain parenchyma, such as skull fractures, intracranial hemorrhage, compression/deformation of nerve tissue, diffuse axonal injury, and crushing of blood vessels. Biochemical, cellular, and physiological alterations induced by primary damage propagate from the impact core to the peripheral area and aggravate brain injury (secondary damage) [1][2]. Pathological events that induce secondary damage in TBI around the impact core include excitotoxicity, cerebral hypoperfusion, brain edema, and neuroinflammation. While primary damage is irreversible and difficult to reduce, secondary damage is partly reversible and remediable. Therefore, therapies for TBI in the acute phase focus on reducing secondary damage. Current treatments for the acute phase of TBI include decompressive craniotomy, hyperosmolar treatment, barbiturates, sedation, and hypothermia therapy. However, these treatments are insufficient and may have adverse effects in some cases. Several candidate drugs have shown beneficial effects in preclinical studies using experimental TBI animal models, but clinical trials have failed to show significant effects in patients with TBI [3][4][5]. In addition, for TBI patients with sequelae, treatments to promote the recovery of neurological functions impaired by TBI are required, which are currently performed by physical therapy. Although many studies have shown that physical therapy promotes synaptic regeneration in damaged nervous systems [6][7][8], no medication is clinically used to enhance its efficiency. Therefore, research and development of medicines applied in the acute and recovery phases of TBI have been extensively conducted.
Many studies have clarified the roles of astrocytes in nerve damage and recovery processes in several brain disorders, including TBI [9][10][11]. Based on these studies, the regulation of astrocytic functions has been proposed as a novel therapeutic strategy for TBI. Endothelin (ET) is one of the factors regulating the pathophysiological functions of astrocytes in damaged nerve tissues [12]. ET receptor signaling-mediated pathophysiological reactions include ischemia, neuropathic pain, and disruption of the blood–brain barrier (BBB) [12].

2. Pathophysiological Responses of Astrocytes to TBI

In response to brain disorders, astrocytes change their phenotype to that of reactive astrocytes, which are characterized by increased glial fibrillary acidic protein (GFAP) expression and hypertrophy. Reactive astrocytes are involved in the progression of many brain pathologies and the regeneration of the injured nervous system. In patients with TBI, phenotypic conversion to reactive astrocytes is predominantly observed in damaged areas [13]. Similarly, reactive astrocytes were also increased in experimental TBI model animals [13][14][15][16]. Brain edema occurs during the acute phase of TBI. Increased intracranial pressure accompanied by brain edema causes impairment of the nervous system and often results in the death of patients with TBI. In addition, neuroinflammation in the acute phase exacerbates neuronal damage caused by TBI and causes various neurological dysfunctions in patients affecting motor, sensory, and cognitive activities. Disruption of the BBB underlies the development of brain edema and neuroinflammation caused by TBI. That is, the hyperpermeability of brain microvascular endothelial cells, which constitute the BBB, can allow the infiltration of inflammatory cells and serum proteins into the cerebral parenchyma damaged by TBI. Astrocytes support the integrity of the BBB, and their end feet surround a large part of the basolateral side of brain microvessels. The permeability of brain microvascular endothelial cells responsible for the BBB is regulated by their interaction with astrocytes. Functional alterations in astrocytes in TBI lead to excessive hyperpermeability of the BBB, which allows the entry of inflammatory cells and serum proteins (Figure 1).
Cells 12 00719 g001 550
Figure 1. Involvement of astrocytes in BBB disruption in the acute phase of traumatic brain injury (TBI). In the acute phase of TBI, activation of astrocytes occurs around the damaged brain area. The astrocytic activation is accompanied by increased expressions of astrocyte-derived vascular permeability factors, such as vascular endothelial growth factor-A (VEGF-A), matrix metalloproteinase 9 (MMP9), and chemokines. This impairs the barrier function of the blood–brain barrier (BBB) and allows entry of inflammatory cells and serum proteins into the brain parenchyma, which leads to neuroinflammation and brain edema.
Increased production of various cytokines and chemokines in the acute phase of TBI has been reported [17][18]. The production of astrocytic cytokines and chemokines is stimulated by several signaling molecules released from damaged cells [19][20][21]. In TBI, astrocytic IL-33 is increased in the human and mouse brain and promotes the accumulation of microglia/macrophages at the site of injury [22]. Xue et al. [23] showed that astrocytes produce C-C Motif Chemokine Ligand 7 (CCL7), which promotes microglia-mediated inflammation in a TBI rat model. Other astrocytic vascular permeability regulators, such as matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor-A (VEGF-A), are also upregulated by TBI and cause disruption of the BBB [14][24][25][26][27]. These results indicate that astrocytes have a detrimental effect on BBB function during the acute phase of TBI. However, some reports suggest that astrocytes have supporting roles in BBB function, by which brain edema and neuroinflammation in TBI are reduced. Hu et al. [28] showed that the ablation of astrocytes exacerbated the infiltration of monocytes into the cerebral parenchyma and neuronal loss in mice with brain stab injuries. Gao et al. [29] found that programmed cell death 1 (PD-L1) signaling in reactive astrocytes prevented excessive neuroimmune and neuronal damage in a controlled cortical impact-induced TBI mouse model. Astrocyte-derived exosomes also protect hippocampal neurons by suppressing mitochondrial oxidative stress and apoptosis in rats with TBI [30]. It also can be found that astrocyte-derived vascular protective factors, such as angiopoietin-1 (ANG-1) and sonic hedgehog (SHH), were increased in TBI model mice [31][32]. These findings suggest that astrocytes suppress TBI-induced neuroinflammation and BBB disruption and exert protective actions against neuronal damage in TBI. Additionally, expression levels of MMP-9 and VEGF-A increased at 6 h to 5 days after TBI, whereas expression levels of ANG-1 and SHH increased at 3 to 10 days after TBI [14][31][32]. This finding shows a possibility that conversion to reactive astrocytes enhances both detrimental and supportive actions on BBB function depending on the phase of TBI.
During the recovery phase of TBI, new synapses are formed in damaged areas, which are supported by neurogenesis from neural progenitors and axonal elongation [33]. This remodeling of the damaged nervous system is the mechanism that underlies the recovery of brain functions impaired by TBI. Some astrocyte-derived factors have been shown to promote the remodeling of the nervous system damaged by TBI. Astrocyte-produced apolipoprotein E [34] and S100b [35] promote neurogenesis and recovery of cognitive function impairments in TBI. Thrombospondins (TSPs) are astrocyte-secreted proteins that promote synaptogenesis [36][37]. Cheng et al. reported that TSP-1 was increased in TBI and that TSP-1 knockout mice exhibited significantly worse neurological deficits in motor and cognitive functions [38]. Production of neurotrophin family neurotrophic factors is upregulated by TBI and promotes neuroprotection in the acute phase, as well as regeneration in the recovery phase [39]. Astrocytes are the major source of nerve growth factor (NGF), which is also upregulated by TBI [40]. Administration of NGF to the rat brain reversed the decrease in cholinergic nerves induced by TBI and enhanced cognitive function [41]. Treatment to increase the production of brain-derived neurotrophic factor (BDNF) in astrocytes restored neuronal function impaired by TBI [42][43]. Hao et al. showed that exogenous neurotrophin-3 (NT-3) administration to TBI model rats promoted neural stem cell proliferation and synaptogenesis [44]. These findings indicate that the ability of astrocytes to produce neurotrophic factors is beneficial in promoting nerve regeneration during the recovery phase of TBI.

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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Shotaro Michinaga
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Shigeru Hishinuma
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Yutaka Koyama
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Update Date: 09 Mar 2023
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