Abstract
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.
Highlights
Astrocytes are the most abundant glial cells in the brain and play roles in supplying nutrients to nerve cells, in reinforcing synaptic structures at nerve endings, and in supporting the limited entry of blood components [1,2]
LeComte et al showed that the transcription of Endothelin B (ETB) receptors was promoted by Stat3, suggesting that this mechanism underlies the upregulation of astrocytic ETB receptors in brain ischemia [95]
It was not examined if the protective action of IRL-1620 against cerebral ischemia is caused by astrocyte-derived growth factors, these observations suggest that the activation of astrocytic ETB receptors is beneficial in promoting the recovery of nerve functions after brain ischemia
Summary
Astrocytes are the most abundant glial cells in the brain and play roles in supplying nutrients to nerve cells, in reinforcing synaptic structures at nerve endings, and in supporting the limited entry of blood components [1,2]. Increased ET-1 in the brain causes various pathophysiological reactions in the injured nervous system, including exacerbation of neuroinflammation [31], vasospasm-mediated ischemic injury [32], angiogenesis [33], and neurogenesis [34,35,36]. Transcription of ET-1 is promoted by transcription factors including AP-1, GATA-2, Smad, HIF-1α, and NFkB [50], for which the binding sites are present in the 5 -flanking region of the gene These transcription factors are activated by cytokines and hormones and by pathological conditions such as hypoxia [51] and mechanical stress [16], which underlie the increase in ET-1 production under pathological conditions. The role of ECEs in AD pathology has been investigated from the perspective of ET production and degradation of amyloid-β proteins [14,54]
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