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Antagonism of purinergic signalling improves recovery from traumatic brain injury

Anthony M. Choo, William J. Miller, Yung-Chia Chen, Philip Nibley, Tapan P. Patel, Cezar Goletiani, Barclay Morrison, Melinda K. Kutzing, Bonnie L. Firestein, Jai-Yoon Sul, Philip G. Haydon, David F. Meaney
DOI: http://dx.doi.org/10.1093/brain/aws286 First published online: 4 January 2013

Summary

The recent public awareness of the incidence and possible long-term consequences of traumatic brain injury only heightens the need to develop effective approaches for treating this neurological disease. In this report, we identify a new therapeutic target for traumatic brain injury by studying the role of astrocytes, rather than neurons, after neurotrauma. We use in vivo multiphoton imaging and show that mechanical forces during trauma trigger intercellular calcium waves throughout the astrocytes, and these waves are mediated by purinergic signalling. Subsequent in vitro screening shows that astrocyte signalling through the ‘mechanical penumbra’ affects the activity of neural circuits distant from the injury epicentre, and a reduction in the intercellular calcium waves within astrocytes restores neural activity after injury. In turn, the targeting of different purinergic receptor populations leads to a reduction in hippocampal cell death in mechanically injured organotypic slice cultures. Finally, the most promising therapeutic candidate from our in vitro screen (MRS 2179, a P2Y1 receptor antagonist) also improves histological and cognitive outcomes in a preclinical model of traumatic brain injury. This work shows the potential of studying astrocyte signalling after trauma to yield new and effective therapeutic targets for treating traumatic brain injury.

  • neuroprotection
  • calcium waves
  • in vivo imaging
  • MRS 2179
  • astrocytes
  • Abbreviations
    BAPTA-AM
    1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)
    PPADS
    pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid
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