Modulating Astrocyte Transition after Stroke to Promote Brain Rescue and Functional Recovery: Emerging Targets Include Rho Kinase

Abstract

Stroke is a common and serious condition, with few therapies. Whilst previous focus has been directed towards biochemical events within neurons, none have successfully prevented the progression of injury that occurs in the acute phase. New targeted treatments that promote recovery after stroke might be a better strategy and are desperately needed for the majority of stroke survivors. Cells comprising the neurovascular unit, including blood vessels and astrocytes, present an alternative target for supporting brain rescue and recovery in the late phase of stroke, since alteration in the unit also occurs in regions outside of the lesion. One of the major changes in the unit involves extensive morphological transition of astrocytes resulting in altered energy metabolism, decreased glutamate reuptake and recycling, and retraction of astrocyte end feed from both blood vessels and neurons. Whilst globally inhibiting transitional change in astrocytes after stroke is reported to result in further damage and functional loss, we discuss the available evidence to suggest that the transitional activation of astrocytes after stroke can be modulated for improved outcomes. In particular, we review the role of Rho-kinase (ROCK) in reactive gliosis and show that inhibiting ROCK after stroke results in reduced scar formation and improved functional recovery.

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

“…Astrocytes play key roles in normal brain function [2, 31]. Upon central nervous system (CNS) injury, astrocytes act as first responders and become activated in injured tissue where they play different, and at times conflicting, roles [2, 29, 31].…”

“…Upon central nervous system (CNS) injury, astrocytes act as first responders and become activated in injured tissue where they play different, and at times conflicting, roles [2, 29, 31]. On the one hand, astrocytes provide energy substrates to neurons, remove excitotoxins in the microenvironment, and promote recovery; on the other, once activated, they initiate an inflammatory response [9, 13, 31] which becomes amplified through the production of chemokines and recruitment of additional glial cells and immune cells [13, 35].…”

“…We have previously shown that many of these targets are positively regulated by HuR in astrocytes and microglia, including TNF-α, IL-6, IL-1β and MMP-12 [22, 25]. In the acute phase, astrocyte activation can disrupt the blood-brain barrier and/or facilitate the development of edema through the secretion of these factors [2, 6, 13, 17, 31]. In the current study, we observed increased vascular permeability and hemispheric edema in HuR Tg mice, despite the lack of a transgene-mediated increase in infarct size.…”

Tetramethylpyrazine Protects Against Oxygen-Glucose Deprivation-Induced Brain Microvascular Endothelial Cells Injury via Rho/Rho-kinase Signaling Pathway

“…Astrocytes, by enwrapping their end feet around the brain microvessels, have been described to be the mediators conveying signals from neurons to the microvessels (Abeysinghe et al 2016). Additionally, astrocytes actively participate in the BBB disruption if they become overactivated, while inhibition of ROCK pathway by fasudil can stabilize astrocytes after stroke by retaining their trophic reactive phenotype without over activation and scar formation (Abeysinghe et al 2016). Considering the importance of astrocytes, targeting of astrocytes may also be a new approach to treating stroke.…”

Regulatory T Cells: Pathophysiological Roles and Clinical Applications

“…7). 104 Although astrogliosis is necessary for forming scar tissue to protect neuronal cells from necrotic areas, excessive activation of astrocytes increases neurotoxic factors, resulting in neural cell damage and inhibition of neuronal outgrowth. 105 Inflammatory cytokines such as IL-6 are important for the activation of astrocytes, 106 and brain Tregs suppress IL-6 levels in vivo and in vitro.…”