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Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
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Novel P2X4 Receptor Antagonist MRS4719 Improves Ischemia/reperfusion Injury in Mice
Rajkumar Verma1, Jinting Zhang2, Sanjeev Kumar Yadav3
1Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, 06030, USA. raverma@uchc.edu.
Abstract:
Ischemic injury triggers extracellular ATP release, activating P2X4 receptors (P2 × 4R) on immune and cardiac cells, which exacerbates inflammation and tissue damage. We evaluated MRS4719, a selective P2 × 4R antagonist, in aged mice subjected to transient middle cerebral artery occlusion (tMCAo) and cardiac ischemia/reperfusion (CI/R) injury. MRS4719 exhibited a nonlinear dose response, with an intermediate dose (2.25 mg/kg/day) and short-term treatment (2 days) optimally improving sensorimotor and cognitive recovery while reducing brain tissue atrophy. Treatment initiated up to 12 h post-stroke significantly decreased infarct volume. Additionally, MRS4719 preserved cardiac contractile function following ischemia/reperfusion injury. These findings suggest that targeted P2X4R inhibition mitigates inflammatory injury across multiple organs and supports functional recovery, highlighting MRS4719's therapeutic potential for cerebral and cardiac ischemic disorders.
Insights
MRS4719, a P2X4 receptor antagonist, improved recovery from brain and heart injury in mice. This drug shows therapeutic potential for ischemic disorders by reducing inflammation and tissue damage.
Area of Science:
- Neuroscience
- Cardiology
- Immunology
Background:
- Ischemic injury causes extracellular ATP release, activating P2X4 receptors (P2X4R).
- P2X4R activation on immune and cardiac cells exacerbates inflammation and tissue damage.
- Targeting P2X4R may offer a novel therapeutic strategy for ischemic conditions.
Purpose of the Study:
- To evaluate the efficacy of MRS4719, a selective P2X4R antagonist, in models of cerebral and cardiac ischemia.
- To determine the optimal dose and treatment duration for MRS4719.
- To assess the impact of MRS4719 on functional recovery and tissue protection.
Main Methods:
- Aged mice underwent transient middle cerebral artery occlusion (tMCAo) for stroke and cardiac ischemia/reperfusion (CI/R) for heart injury.
- MRS4719 was administered at various doses and treatment durations.
- Sensorimotor, cognitive function, brain tissue atrophy, infarct volume, and cardiac contractile function were assessed.
Main Results:
- MRS4719 demonstrated a nonlinear dose response, with an intermediate dose (2.25 mg/kg/day) and short-term treatment (2 days) yielding optimal sensorimotor and cognitive recovery.
- Treatment with MRS4719 significantly reduced brain tissue atrophy and infarct volume when initiated up to 12 hours post-stroke.
- MRS4719 preserved cardiac contractile function following CI/R injury.
Conclusions:
- Targeted P2X4R inhibition with MRS4719 mitigates inflammatory injury in both cerebral and cardiac tissues.
- MRS4719 promotes functional recovery after ischemic events.
- MRS4719 exhibits significant therapeutic potential for treating cerebral and cardiac ischemic disorders.
