Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus

J Neuroinflammation. 2012 Apr 18;9:69. doi: 10.1186/1742-2094-9-69.

Abstract

Background: Neuroinflammation 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.

Methods: Immediately 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.

Results: The 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.

Conclusions: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / pathology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Inflammation Mediators / administration & dosage*
  • Inflammation Mediators / physiology
  • Injections, Intraventricular
  • Ischemic Attack, Transient / pathology*
  • Ischemic Attack, Transient / prevention & control*
  • Male
  • Neuroprotective Agents / administration & dosage
  • Purinergic P2X Receptor Antagonists / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X7 / metabolism*
  • Reperfusion Injury / pathology*
  • Reperfusion Injury / prevention & control*

Substances

  • Inflammation Mediators
  • Neuroprotective Agents
  • Purinergic P2X Receptor Antagonists
  • Receptors, Purinergic P2X7