The role of the astrocyte in subarachnoid hemorrhage and its therapeutic implications

Abstract

Subarachnoid hemorrhage (SAH) is an important public health concern with high morbidity and mortality worldwide. SAH induces cell death, blood-brain barrier (BBB) damage, brain edema and oxidative stress. As the most abundant cell type in the central nervous system, astrocytes play an essential role in brain damage and recovery following SAH. This review describes astrocyte activation and polarization after SAH. Astrocytes mediate BBB disruption, glymphatic-lymphatic system dysfunction, oxidative stress, and cell death after SAH. Furthermore, astrocytes engage in abundant crosstalk with other brain cells, such as endothelial cells, neurons, pericytes, microglia and monocytes, after SAH. In addition, astrocytes also exert protective functions in SAH. Finally, we summarize evidence regarding therapeutic approaches aimed at modulating astrocyte function following SAH, which could provide some new leads for future translational therapy to alleviate damage after SAH.

Keywords: astrocyte; astrocyte activation; blood-brain barrier; cell death; glymphatic-meningeal lymphatic system; neurovascular unit; oxidative stress; subarachnoid hemorrhage.

Figure 1

Morphological and functional changes in astrocytes after SAH. (A) Astrocytes are activated into predominant neurotoxic A1 subtype after SAH. (B) Astrocytes are involved in the disruption of BBB integrity due to SAH, leading to the leakage of circulatory neurotoxic substances into the parenchyma. (C) Astrocytes-constituted glymphatic-lymphatic system is impaired due to the hemorrhage in subarachnoid space, resulting in subsequent brain edema. The polarity of AQP4 in astrocytic endfeet is decreased after SAH. (D) Excess ROS in astrocytes is related to the oxidative stress after SAH, in which iNOS, Nox2, and Nox4 play critical roles. (E) The apoptosis of astrocytes occurs earlier than neurons after SAH, probably in a caspase-dependent manner.

Figure 2

Reactive astrocytes play a neuroprotective role in recovery stage after SAH. Reactive astrocytes release several cell cytokines, playing a neuroprotective role after SAH. (A) HIF accelerates the angiogenesis possibly via WNT signaling pathway. (B) PDGF-BB facilitates the recovery of synapses between neural cells. (C) CD24 participates in the axon regeneration after the insult. (D) And BDNF promotes the proliferation, differentiation, and migration of neural stem cells.