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Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats.

ABSTRACT: Traumatic brain injury (TBI) is the leading cause of death and disability for people under the age of 45 years worldwide. Neuropathology after TBI is the result of both the immediate impact injury and secondary injury mechanisms. Secondary injury is the result of cascade events, including glutamate excitotoxicity, calcium overloading, free radical generation, and neuroinflammation, ultimately leading to brain cell death. In this study, the P2X7 receptor (P2X7R) was detected predominately in microglia of the cerebral cortex and was up-regulated on microglial cells after TBI. The microglia transformed into amoeba-like and discharged many microvesicle (MV)-like particles in the injured and adjacent regions. A P2X7R antagonist (A804598) and an immune inhibitor (FTY720) reduced significantly the number of MV-like particles in the injured/adjacent regions and in cerebrospinal fluid, reduced the number of neurons undergoing apoptotic cell death, and increased the survival of neurons in the cerebral cortex injured and adjacent regions. Blockade of the P2X7R and FTY720 reduced interleukin-1?expression, P38 phosphorylation, and glial activation in the cerebral cortex and improved neurobehavioral outcomes after TBI. These data indicate that MV-like particles discharged by microglia after TBI may be involved in the development of local inflammation and secondary nerve cell injury.

SUBMITTER: Liu X

PROVIDER: S-EPMC5714842 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats.

Liu Xiaofeng X Zhao Zhengqing Z Ji Ruihua R Zhu Jiao J Sui Qian-Qian QQ Knight Gillian E GE Burnstock Geoffrey G He Cheng C Yuan Hongbin H Xiang Zhenghua Z

Purinergic signalling 20170819 4

Traumatic brain injury (TBI) is the leading cause of death and disability for people under the age of 45 years worldwide. Neuropathology after TBI is the result of both the immediate impact injury and secondary injury mechanisms. Secondary injury is the result of cascade events, including glutamate excitotoxicity, calcium overloading, free radical generation, and neuroinflammation, ultimately leading to brain cell death. In this study, the P2X7 receptor (P2X7R) was detected predominately in micr ...[more]

PMID: 28823092

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Project description:BackgroundInjuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2?, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.MethodsAccordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.ResultsMorphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.ConclusionThis study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.

Project description:There is a significant need for novel treatments that will improve traumatic brain injury (TBI) outcomes. One potential neuroprotective mechanism is to increase oxygen binding proteins such as neuroglobin. Neuroglobin has a high affinity for oxygen, is an effective free radical scavenger, and is neuroprotective within the brain following hypoxia and ischemia. The purpose of this study was to determine whether neuroglobin overexpression improves sensorimotor outcomes following TBI in transgenic neuroglobin overexpressing (NGB) mice. Additional study aims were to determine if and when an endogenous neuroglobin response occurred following TBI in wild-type (WT) mice, and in what brain regions and cell types the response occurred. Controlled cortical impact (CCI) was performed in adult (5 month) C57/BL6 WT mice, and NGB mice constitutively overexpressing neuroglobin via the chicken beta actin promoter coupled with the cytomegalovirus distal enhancer. The gridwalk task was used for sensorimotor testing of both WT and NGB mice, prior to injury, and at 2, 3, and 7 days post-TBI. NGB mice displayed significant reductions in the average number of foot faults per minute walking at 2, 3, and 7 days post-TBI when compared to WT mice at each time point. Neuroglobin mRNA expression was assessed in the injured cortex of WT mice prior to injury, and at 1, 3, 7, and 14 days post-TBI using quantitative real time polymerase chain reaction (qRT-PCR). Neuroglobin mRNA was significantly increased at 7 days post-TBI. Immunostaining showed neuroglobin primarily localized to neurons and glial cells in the injured cortex and ipsilateral hippocampus of WT mice, while neuroglobin was present in all brain regions of NGB mice at 7 days post-TBI. These results showed that overexpression of neuroglobin reduced sensorimotor deficits following TBI, and that an endogenous increase in neuroglobin expression occurs during the subacute period. Increasing neuroglobin expression through novel therapeutic interventions during the acute period after TBI may improve recovery.

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Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats.

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Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats.

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