<EM>IN VIVO</EM> MULTIMODAL IMAGING OF PURINERGIC P2X7 RECEPTOR INVOLVEMENT IN THE ISCHEMIC RESPONSE IN A RAT MODEL OF STROKE

Ischemic stroke leads to elevated extracellular adenosine 5’-triphosphate levels, highlighting the relevance of purinergic receptors, particularly the P2X7 receptor (P2X7R), as potential therapeutic targets¹. As their diagnostic and therapeutic value remains poorly characterized, this study aimed to longitudinally assess in vivo P2X7R expression in healthy and ischemic rats and to investigate its role in ischemic response using non-invasive imaging approaches.
Transient middle cerebral artery occlusion (tMCAO) was induced for 75 minutes, followed by magnetic resonance imaging (MRI) and positron emission tomography (PET) using the selective P2X7R radiotracer [¹⁸F]JNJ-64413739² at baseline and up to one month post-ischemia. Complementary ex vivo analyses were performed to further characterize receptor expression. To evaluate the functional contribution of P2X7R, rats were administered the selective P2X7R antagonist A804598 (2.5 mg/kg) during the first week after ischemia. MRI and PET imaging were conducted on days 3 and 7 to assess neuroinflammation ([¹⁸F]DPA-714), matrix metalloproteinase activation ([¹⁸F]BR-351), and oxidative stress ([¹⁸F]FSPG). Under physiological conditions, P2X7R expression was minimal across brain regions. MRI revealed a cortico-striatal infarction accompanied by a progressive increase in PET-[¹⁸F]JNJ-64413739 signal up to day 7, followed by a subsequent decline in both cortex and striatum. This pattern was consistent with an increased presence of CD11b⁺/P2X7R⁺ microglia/macrophages within the ischemic area. Pharmacological blockade of P2X7R reduced [¹⁸F]DPA-714 uptake and enhanced PET-[18F]BR-351 signal (Fig.1), while no significant differences in oxidative stress were observed. Overall, these findings demonstrate that P2X7R plays a key role in post-ischemic pathophysiology, supporting its potential as a therapeutic target.