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

Interesting discussion of possible hyperacute therapies and the neuronal cascade of death but seems to be no useful translational protocols available for use by survivors.
http://www.mdpi.com/1422-0067/17/3/288/htm

Hima Charika S. Abeysinghe ^1,2, Ellie L. Phillips ³, Heung Chin-Cheng ³, Philip M. Beart ⁴ and Carli L. Roulston ^1,*

¹

Neurotrauma Research, Department of Medicine, St Vincent’s Campus, University of Melbourne, Parkville, VIC 3065, Australia

²

Department of Surgery, St Vincent’s Campus, University of Melbourne, Parkville, VIC 3065, Australia

³

Department of Biochemistry and Molecular Biology, Bio21 Insitute, University of Melbourne, Parkville, VIC 3010, Australia

⁴

The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Parkville, VIC 3010, Australia

*

Correspondence: Tel.: +61-3-9288-3242; Fax: +61-3-9416-2581

Academic Editor: Chris Sobey

Received: 30 November 2015 / Accepted: 5 February 2016 / Published: 26 February 2016

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. 

7. Conclusions

Breakdown in the neurovascular unit after stroke involves reactive morphological transition of astrocytes that initially protect the brain against the ischaemic insult but ultimately results in extensive glial scar formation and spread of injury. The glial scar is also a major impediment to the recovery processes through lost neural connectivity in surviving pathways due to breakdown in the neurovascular unit, as well as preventing nerve regeneration through inhibition of axonal growth cone extension. Whilst inhibiting the initial activation of astrocytes after stroke results in bad outcomes, modulating this response might be better approach, where initial responses by astrocytes are preserved, but overall glial scarring reduced. The Rho-kinase pathway is a potential target for modulating this effect. Its inhibitor, Fasudil, has previously been investigated as a potential neuroprotectant following stroke, with positive results. However as ROCK is involved in multiple signaling pathways, it is likely to have an additional mechanism. As such, new evidence suggests that inhibition of ROCK stabilizes astrocytes after stroke by retaining their trophic reactive phenotype without over activation and scar formation, even when treatment is significantly delayed in vivo. This approach results in better long term functional outcomes and importantly highlights the need to address different approaches to treating stroke beyond targeting specific events within neurons.