P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemia

被引:162
作者
Arbeloa, Joana [1 ,2 ]
Perez-Samartin, Alberto [1 ,2 ]
Gottlieb, Miroslav [3 ]
Matute, Carlos [1 ,2 ]
机构
[1] Univ Basque Country, Dept Neurosci, CIBERNED, Leioa 48940, Spain
[2] Univ Basque Country, Dept Neurosci, Neurobiol Lab, Leioa 48940, Spain
[3] Slovak Acad Sci, Inst Neurobiol, Kosice 04001, Slovakia
关键词
Excitotoxicity; Ischemia; Neuronal damage; P2X7; CEREBRAL-ARTERY OCCLUSION; SPINAL-CORD-INJURY; IN-VITRO ISCHEMIA; EXTRACELLULAR ATP; P2X(7) RECEPTORS; CORTICAL-NEURONS; ADENOSINE-TRIPHOSPHATE; HIPPOCAMPAL SLICES; IMPROVES RECOVERY; PLASMA-MEMBRANE;
D O I
10.1016/j.nbd.2011.12.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Overactivation of subtype P2X7 receptors can induce excitotoxic neuronal death by calcium (Ca2+) overload. In this study, we characterize the functional properties of P2X7 receptors using electrophysiology and Ca2+ monitoring in primary cortical neuron cultures and in brain slices. Both electrical responses and Ca2+ influx induced by ATP and benzoyl-ATP were reduced by Brilliant Blue G (BBG) at concentrations which specifically inhibit P2X7 receptors. In turn, oxygen-glucose deprivation (OGD) caused neuronal death that was reduced with BBC application. OGD in neuron cultures and brain slices generated an inward current, which was delayed and reduced by BOG. To assess the relevance of these in vitro findings, we used middle cerebral artery occlusion in rats as a model of transient focal cerebral ischemia to study the neuroprotective effect of BOG in vivo. Treatment with BBG (twice per day, 30 mg/kg) produced a 60% reduction in the extent of brain damage compared to treatment with vehicle alone. These results show that P2X7 purinergic receptors mediate tissue damage after OGD in neurons and following transient brain ischemia. Therefore, these receptors are a relevant molecular target for the development of new treatments to attenuate brain damage following stroke. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:954 / 961
页数:8
相关论文
共 55 条
[1]   Purinergic signalling in the nervous system: an overview [J].
Abbracchio, Maria P. ;
Burnstock, Geoffrey ;
Verkhratsky, Alexei ;
Zimmermann, Herbert .
TRENDS IN NEUROSCIENCES, 2009, 32 (01) :19-29
[2]   P2 receptor modulation and cytotoxic function in cultured CNS neurons [J].
Amadio, S ;
D'Ambrosi, N ;
Cavaliere, F ;
Murra, B ;
Sancesario, G ;
Bernardi, G ;
Burnstock, G ;
Volonté, C .
NEUROPHARMACOLOGY, 2002, 42 (04) :489-501
[3]   Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons [J].
Anderson, CM ;
Nedergaard, M .
TRENDS IN NEUROSCIENCES, 2006, 29 (05) :257-262
[4]   Pannexin membrane channels are mechanosensitive conduits for ATP [J].
Bao, L ;
Locovei, S ;
Dahl, G .
FEBS LETTERS, 2004, 572 (1-3) :65-68
[5]   RAT MIDDLE CEREBRAL-ARTERY OCCLUSION - EVALUATION OF THE MODEL AND DEVELOPMENT OF A NEUROLOGIC EXAMINATION [J].
BEDERSON, JB ;
PITTS, LH ;
TSUJI, M ;
NISHIMURA, MC ;
DAVIS, RL ;
BARTKOWSKI, H .
STROKE, 1986, 17 (03) :472-476
[6]  
Braun N, 1998, J NEUROSCI, V18, P4891
[7]   Historical review: ATP as a neurotransmitter [J].
Burnstock, G .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2006, 27 (03) :166-176
[8]   Cellular distribution and functions of P2 receptor subtypes in different systems [J].
Burnstock, G ;
Knight, GE .
INTERNATIONAL REVIEW OF CYTOLOGY - A SURVEY OF CELL BIOLOGY, VOL. 240, 2004, 240 :31-+
[9]   Physiology and pathophysiology of purinergic neurotransmission [J].
Burnstock, Geoffrey .
PHYSIOLOGICAL REVIEWS, 2007, 87 (02) :659-797
[10]   A novel, rapid, computerised method for quantitation of neuronal damage in a rat model of stroke [J].
Callaway, JK ;
Knight, MJ ;
Watkins, DJ ;
Beart, PM ;
Jarrott, B ;
Delaney, PM .
JOURNAL OF NEUROSCIENCE METHODS, 2000, 102 (01) :53-60