Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood-brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI.

Keywords: astrogliosis; blood–brain barrier; cytotoxic edema; neuroinflammation; traumatic brain injury.

Figure 1

Expected mechanisms on astrogliosis in TBI. TBI promotes the expression of multiple bioactive factors such as endothelin-1 (ET-1) and interleukine-1 (IL-1). ET-1 and IL-1 bind to the ET_B receptor and IL-1 receptor in astrocytes, respectively. Stimuli of these receptors activate the mitogen-activated protein kinase (MAPK) and Ca²⁺-calmodulin (CaM) pathways that promote the expression of glial fibrillary acidic protein (GFAP), cyclin D1, and S-phase kinase-associated protein 2 (Skp2) via activation of transcriptional factors including signal transducer and activator of transcription 3 (STAT3), specificity protein-1 (Sp-1), and nuclear factor-κB (NF-κB) in astrocytes, resulting in astrogliosis.

Figure 2

Responses of astrocytes in TBI and expected actions of the astrocyte-targeting drugs. Resting type of astrocyte converts to reactive type in TBI, resulting in induction of astrogliosis. Reactive astrocytes secrete multiple bioactive factors that exert protective and deleterious actions in central nervous tissue in TBI. In addition, expression of aquaporin-4 (AQP-4) is increased in reactive astrocytes, resulting in the promotion of cytotoxic edema formation. Astrocyte-targeting drugs may attenuate excessive astrogliosis, increase protective factors, decrease deleterious factors, and inhibit excessive AQP-4 function.