http://brain.oxfordjournals.org/content/early/2013/01/04/brain.aws286.abstract
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.
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