Abstract
BackgroundNeuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury. The P2X7 receptor (P2X7R) has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury.MethodsImmediately after infusion with the P2X7R antagonists Brilliant blue G (BBG), adenosine 5′-triphosphate-2′,3′-dialdehyde (OxATP) or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL). In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1β, TNF-α and IL-6, and to identify activated microglia and astrocytes.ResultsThe P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 μg) and A-0438079 (3 μg), and a low dosage of OxATP (1 μg) significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus.ConclusionsOur study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury.
Highlights
Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury
Inhibition of the P2X7 receptor (P2X7R) reduces I/R-induced neuron death and neuronal DNA cleavage To address the potential that inhibiting P2X7R prevents transient global cerebral I/R injury, neuronal survival was observed at +3D and +7D
All three P2X7R antagonists protected against transient global cerebral I/R injury in a dose-dependent manner
Summary
Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury. The role of P2X7Rs in transient global cerebral I/R injury remains unclear. Neuroinflammation, which is characterized by microglial and astroglial activation, as well as the release of cytotoxic agents (cytokines, matrix metalloproteinases, nitric oxide and reactive oxygen species) can be triggered by cerebral I/R injury, which can contribute to blood–brain barrier disruption and delayed neuronal death [3]. These damaged cells release more toxic mediators, which in turn activate more immune cells. Anti-inflammation therapy may become a promising therapeutic strategy for the treatment of cerebral I/R injury [3,4]
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