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.

Download full-text


Available from: Bonnie Firestein,
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroglia, represented by astrocytes, oligodendrocytes, NG glia and microglia are homeostatic, myelinating and defensive cells of the brain. neuroglial cells express various combinations of purinoceptors, which contribute to multiple intercellular signalling pathways in the healthy and diseased nervous system. Neurological diseases are invariably associated with profound neuroglial remodelling, which is manifest by reactive gliosis, pathological remodelling and functional atrophy of various types of glial cells. Gliopathology is disease and region specific and produces multiple glial phenotypes that may be neuroprotective or neurotoxic. In this review we summarise recent knowledge on the role of glial purinergic signalling in cognitive related neurological diseases. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 09/2015; DOI:10.1016/j.neuropharm.2015.08.005 · 5.11 Impact Factor
  • Source
    • "Furthermore,P2X7RsynergisticallyregulateP2Y1Ractivation (Locoveietal.,2006),particularlyinpathologicalconditions (Trainietal.,2011;Vesseyetal.,2011;Chooetal.,2013).Finally, emergingevidenceindicatesasynergicinterplaybetweenATP anditsmetaboliteadenosine(GerwinsandFredholm,1992; Nearyetal.,1998;Chevrieretal.,2006;Färberetal.,2008; Koizumietal.,2013;Georgeetal.,2015),namelybetween "
    [Show abstract] [Hide abstract]
    ABSTRACT: ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
    Frontiers in Neuroscience 04/2015; 9. DOI:10.3389/fnins.2015.00148 · 3.66 Impact Factor
  • Source
    • "Neuronal injuries activate astrocytic P2Y 1 receptors leading to the release of PGE 2 , causing reactive gliosis (Xia and Zhu, 2011), or glutamate, mediating synaptic modulation (Domercq et al., 2006). Blocking of P2Y 1 receptors therefore reduces glial activity (Davalos et al., 2005) and improves cognitive outcome following traumatic brain injury (Choo et al., 2013). In the AD brain, P2Y 1 receptors are localized in the neurofibrillary tangles and neuritic plaques (Moore et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain inflammation is a common occurrence following responses to varied insults such as bacterial infections, stroke, traumatic brain injury and neurodegenerative disorders. A common mediator for these varied inflammatory responses is prostaglandin E2 (PGE2), produced by the enzymatic activity of cyclooxygenases (COX) 1 and 2. Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs), have met with limited success. We are proposing the two-hit model for neuronal injury—an initial localized inflammation mediated by PGE2 (first hit) and the simultaneous release of adenosine triphosphate (ATP) by injured cells (second hit), which significantly enhances the inflammatory response through increased synthesis of PGE2. Several evidences on the role of exogenous ATP in inflammation have been reported, including contrary instances where extracellular ATP reduces inflammatory events. In this review, we will examine the current literature on the role of P2 receptors, to which ATP binds, in modulating inflammatory reactions during neurodegeneration. Targeting the P2 receptors, therefore, provides a therapeutic alternative to reduce inflammation in the brain. P2 receptor-based anti-inflammatory drugs (PBAIDs) will retain the activities of essential COX enzymes, yet will significantly reduce neuroinflammation by decreasing the enhanced production of PGE2 by extracellular ATP.
    Frontiers in Cellular Neuroscience 09/2014; 8:260. DOI:10.3389/fncel.2014.00260 · 4.29 Impact Factor
Show more