Antagonism of purinergic signalling improves recovery from traumatic brain injury

1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Brain (Impact Factor: 9.2). 01/2013; 136(1). DOI: 10.1093/brain/aws286
Source: PubMed


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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    • "Immunoreactivity of P2Y 1 receptors has been shown to be co-localized with GFAP-positive astrocytes, and antagonists for this receptor were beneficial in regulating the cytokine/chemokine response to MCAO. In agreement with these data cognitive deficits after both traumatic brain injury and focal cerebral stroke could be improved by P2Y 1 receptor blockade or genetic ablation (Chin et al., 2013; Choo et al., 2013). As a reason for disturbed cognition, the overt purinergic astrocyte signalling from the penumbra to neural circuits distant from the injury epicentre has been assumed. "
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