title: Antagonism of purinergic signalling improves recovery from traumatic brain injury.
abstract: 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.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Choo
authors.forename: William J
authors.initials: WJ
authors.lastname: Miller
authors.forename: Yung-Chia
authors.initials: YC
authors.lastname: Chen
authors.forename: Philip
authors.initials: P
authors.lastname: Nibley
authors.forename: Tapan P
authors.initials: TP
authors.lastname: Patel
authors.forename: Cezar
authors.initials: C
authors.lastname: Goletiani
authors.forename: Barclay
authors.initials: B
authors.lastname: Morrison
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Kutzing
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Firestein
authors.forename: Jai-Yoon
authors.initials: JY
authors.lastname: Sul
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D058921:Purinergic P2Y Receptor Antagonists; D000244:Adenosine Diphosphate; D002118:Calcium