Abstract
Ischemic injury triggers extracellular ATP release, activating P2X4 receptors (P2X4R) on immune and cardiac cells, which exacerbates inflammation and tissue damage. We evaluated MRS4719, a selective P2X4R 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 hours 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.
Graphical Abstract
INTRODUCTION
Ischemic injury in various organs remains a leading cause of long-term disability globally, but pharmacological strategies that promote recovery beyond reperfusion are limited. A major contributor to post-ischemic injury and impaired recovery is the rapid release of extracellular adenosine triphosphate (ATP) from damaged and dying cells, which activates purinergic P2X receptors on brain resident microglia and infiltrating myeloid cells (1, 2). Among these, the P2X4 receptor (P2X4R) has emerged as a critical regulator of inflammatory disease such as pain and stroke (2, 3). The medicinal chemistry and structural biology of this receptor have been extensively explored, and multiple chemotypes have been identified among its antagonists (4–7).
Blocking the P2X4R has been shown to be efficacious in treating neuropathic pain and acute kidney injury (8, 9). We previously showed that P2X4R is highly expressed on microglia and peripheral monocytes and is rapidly upregulated following ischemic stroke injury (10). Excessive ATP-mediated P2X4R activation amplifies inflammatory signaling, disrupts the blood-brain barrier, and leads to subsequent neuronal injury during the acute phase of stroke (10). Notably, P2X4R signaling is also involved in later reparative processes, such as neurotrophic factor release and synaptic remodeling (2), highlighting its dual role in injury and recovery. Furthermore, we have found that P2X4R contributes to pathological processes in cardiac ischemia/reperfusion (I/R) injury as well (11), indicating that P2X4R activation following ischemic injury is detrimental in multiple organ systems.
We previously demonstrated that novel P2X4R inhibitors reduced acute ischemic injury and improved long-term functional recovery when administered shortly after ischemia. Among these inhibitors, we found that MRS4719, a potent receptor-selective P2X4R antagonist, reduced stroke injury in both young and aged mice and improved memory in aged mice (12). However, we did not evaluate how varying the dose, duration, and timing of MRS4719 administration impacted stroke outcomes across various functional tasks, including sensorimotor learning and memory,. Furthermore, we had not yet assessed whether MRS4719 has a protective effect in cardiac ischemia/reperfusion injury.
Here, we systematically examined how the dose, duration, and timing of MRS4719 administration impacted stroke outcomes in an established mouse model of ischemic stroke. Additionally, we assessed whether MRS4719 was protective against cardiac dysfunction in a cardiac ischemia/reperfusion injury model. In the stroke model, we evaluated sensorimotor, cognitive, affective, and histological outcomes to define an optimal therapeutic regimen. We demonstrate that the MRS4719 dose response is nonlinear, short-term administration is sufficient to improve outcomes, and treatment can be delayed up to 12 hrs. post-stroke and still confer significant benefits. Furthermore, we show that MRS4719 preserves cardiac function following I/R injury, indicating that P2X4R inhibition is protective in multiple organ systems affected by ischemia. Therefore, this work is novel as systematically defining the dose, duration, and timing of MRS4719 treatment was not addressed in our prior studies, which used fixed conditions with limited translational value. This approach is critical as it identifies the therapeutic window and optimal regimen, improving rigor, reproducibility, and clinical relevance.
RESULTS
Dose-dependent effects of early MRS4719 treatment on post-stroke functional recovery
To determine whether the therapeutic efficacy of MRS4719 depends on dose following ischemic injury, mice subjected to 60 min transient middle cerebral artery occlusion (tMCAo) were treated with escalating doses of MRS4719 (1.5, 2.25, or 3.0 mg/kg/day) for three consecutive days beginning early after reperfusion (4 hrs. post-MCAo). Functional and histological outcomes were assessed during the recovery phase at various time interval (rotarod at days 2–28) as in the schematic (Supplementary Figure 1). We selected a 3-day treatment duration and a dose range of 1.5–3.0 mg/kg/day based on our prior published data, which showed that 3-day treatment with MRS4719 at 1.5 mg/kg/day improved stroke outcomes (12).
Sensorimotor recovery
Sensorimotor performance was evaluated using the rotarod test. We did not see a clear dose-dependent effect on the rotarod task using multigroup analysis (Fig 1A). However, mice receiving 2.25 mg/kg/day demonstrated a significant increase in latency to fall compared with vehicle-treated controls when used pairwise analysis between these two groups, indicating improved motor coordination and balance at this dose.
Figure 1.
Dose dependent effect of MRS4719 (dose × 3 days duration by Alzet minipump) on long term behavioral recovery after stroke. A) At a dose of 2.25 mg/kg bw/day improved sensorimotor during progressive recovery as shown by increase in latency to fall time (*p<0.05 vs Veh, One-way Anova followed by Tukey’s multiple comparison test). B) A dose of 1.5 and 2.25 mg/kg bw/day showed reduced tissue atrophy measured at 30 days after stroke, while a higher dose 3 mg/kg show no effect on atrophy (n=5–15/treatment group = 50 mice total; 28 males and 22 females). Data are mean±S.D.
Attenuation of post-stroke tissue atrophy
Histological analysis performed 30 days post-stroke revealed significant differences in tissue preservation (reduced tissue atrophy) across treatment groups. Compared with vehicle-treated mice, animals receiving 1.5 or 2.25 mg/kg/day MRS4719 exhibited significant preservation of ipsilateral tissue, reflecting reduced post-stroke atrophy. In contrast, the highest dose (3.0 mg/kg/day) did not confer significant histological protection. These data further support a non-linear dose-response profile, with the lower and intermediate doses providing greater brain tissue preservation after stroke (Fig. 1B).
Effect of MRS4719 treatment duration on post stroke functional outcomes.
Sensorimotor recovery
Given the non-linear dose-response observed with 3-day treatment and the differential effects on functional versus histological outcomes, we next examined whether the duration of MRS4719 administration influences post-stroke recovery. Mice subjected to 60 min tMCAo were treated with MRS4719 (1.5 mg/kg/day; treatment onset 4 hrs. post-MCAo) for 2, 3, or 7 days, and sensorimotor function was assessed longitudinally using the rotarod test (Fig. 2A). Vehicle-treated mice displayed sustained impairments in rotarod performance throughout the recovery period, with only partial spontaneous improvement. In contrast, mice receiving MRS4719 for 2 days exhibited a significant increase in latency to fall compared with vehicle-treated controls (p < 0.05; one-way ANOVA with Tukey’s multiple comparisons test). This improvement emerged early during recovery and was maintained throughout subsequent testing sessions. Extending MRS4719 treatment to 3 or 7 days did not result in further improvement and, in the case of 7 days, was associated with greater variability and lower overall performance relative to the 2-day treatment group. These findings indicate that short-term MRS4719 administration (2 days post-MCAo) optimally supports long-term sensorimotor recovery following ischemic stroke.
Figure 2.
Effect of duration of MRS4719 (1.5 mg/kg bw/day) treatment on long term behavioral recovery. A) Short term treatment for two days improved sensorimotor during progressive recovery as shown by increase in latency to fall time (*p<0.05 vs Veh). B) Memory and learning measured by the Novel Object Recognition Test showed increased memory retention with a 2-day treatment. C) Both 2- and 3-day treatment reduced tissue atrophy measured at 30 days after stroke. (n=5–15/treatment group = 50 mice total; 28 males and 22 females). Data were analyzed by one-way Anova followed by Tukey’s multiple comparison test and presented as mean ± S.D. MCAo, middle cerebral artery occlusion, DT, days of treatment. Each dot represents an individual mouse.
Learning and memory
To assess whether treatment duration similarly influences cognitive outcomes, learning and memory were evaluated using the novel object recognition test (NORT) after stroke. Vehicle-treated mice exhibited impaired recognition memory, as indicated by a low discrimination index. Mice receiving MRS4719 for 2 days showed a significant improvement in discrimination index compared with vehicle-treated controls (p < 0.05; one-way ANOVA with Tukey’s post hoc test). In contrast, extending the treatment to 3 or 7 days did not produce additional improvement and resulted in increased inter-animal variability (Fig. 2B).
Post-stroke tissue atrophy
Both 2- and 3-day treatment reduced brain tissue atrophy after MRS4719 treatment, while a 7-day treatment regimen showed a trend toward reduced atrophy (Fig. 2C), further confirming our observation that short term treatment with a P2X4R inhibitor provides optimal neuroprotection.
Summary of dose- and duration-dependent effects of MRS4719
Together, these results demonstrate that MRS4719 exerts nonlinear dose- and duration-dependent effects on post-stroke recovery. Intermediate dosing (2.25 mg/kg/day) during a 3-day treatment period maximally improved sensorimotor performance, whereas lower and intermediate doses preserved cortical tissue. Shortening the treatment duration to 2 days enhanced both long-term sensorimotor and cognitive recovery, while prolonged administration did not confer additional benefit.
Based on the observed nonlinear dose-response relationship, an intermediate dose of 2.25 mg/kg/day produced the most consistent improvement in sensorimotor and cognitive outcomes without loss of tissue protection. Duration studies further demonstrated that 2 days of treatment was sufficient to confer sustained functional benefits, whereas longer treatment did not necessarily enhance recovery and rather increased variability in data. Together, these findings identify 2.25 mg/kg/day for 2 days as a desired regimen that captures the peak functional efficacy of MRS4719 while minimizing unnecessary drug exposure, supporting its use in subsequent studies.
Effect of delay in MRS4719 treatment on post stroke outcome
Given that a wider therapeutic window would be highly translational for post stroke therapy, we further tested if a dose of 2.25 mg/kg/day × 2 days of MRS4719 given at either 4, 8, or 12 hrs. after the onset of MCAo can reduce infarct injury after stroke. Treatment was ceased at 48 hrs. after MCAo onset, and mice were sacrificed at 72 hrs. (day 3) post-MCAo to remove the brain and perform TTC staining. Interestingly, we found that treatment delayed by 4–12 hrs. significantly reduced infarct injury, suggesting its efficacy is preserved even with delayed onset of treatment (Fig. 3).
Figure 3.
TTC infarct volume analysis after ischemic stroke with delayed treatment. Quantification of infarct volume (% contralateral hemisphere) measured by TTC staining in animals treated with vehicle (red) or MRS4719 (2.25 mg/kg bw/day for 2 days; blue) at different treatment delays after stroke onset (4, 8, and 12 HD; HD, hrs. delay). Each dot represents an individual subject; bars show mean ± SEM. Statistical significance between vehicle and MRS4719 groups at each time point was assessed using unpaired t-tests; *p < 0.05 vs Vehicle.
MRS4719 Preserves Cardiac Contractile Function Following I/R Injury
To evaluate the effect of vehicle control (PBS) or MRS4719 on cardiac function following myocardial I/R injury. Briefly myocardial I/R injury was induced in wild-type (WT) mice as previously described (2), with minor modifications. Successful ischemia was confirmed by immediate blanching of the anterior left ventricular wall. After 30 minutes of ischemia, reperfusion was initiated by releasing the ligature and removing the PE-10 tubing. Restoration of myocardial color confirmed successful reperfusion. Echocardiographic parameters were analyzed as within-animal changes by calculating delta values (Δ), defined as the difference between post-I/R and pre-I/R measurements for each mouse and this value was used to compare vehicle and MRS4719 treatment groups for various time point (24–48 hrs.). This approach minimized inter-animal variability and enabled the direct assessment of functional decline or recovery following injury (Fig. 4). Our data suggests a significant preservation of heart contractility after MRS4719 treatment following cardiac I/R injury. Collectively, these data demonstrate that pharmacological inhibition of the P2X4R with MRS4719 significantly mitigates cardiac dysfunction after I/R and preserves ventricular systolic performance during the early reperfusion period.
Figure 4.
MRS4719 preserved left ventricular systolic function following myocardial ischemia/reperfusion injury. Transthoracic echocardiography was performed in wild-type mice at baseline (pre-I/R) and at 24, 36, or 48 hrs. (h) following myocardial I/R injury. Cardiac function was analyzed as within-animal changes, calculated as delta (Δ) values representing the difference between pre-I/R and post-I/R measurements for each individual mouse, thereby minimizing inter-animal variability (A) ΔEjection Fraction (ΔEF, %) calculated as Post-I/R EF minus pre-I/R EF at the indicated reperfusion time points in vehicle-treated (PBS) and MRS4719-treated mice. Positive ΔEF values indicate a decline in systolic function following I/R injury, whereas negative values indicate preservation or improvement of EF relative to baseline. (B) ΔFractional Shortening (ΔFS, %) calculated as post-I/R FS minus pre-I/R FS at the corresponding time points. Similar to EF, positive ΔFS values reflect I/R-induced impairment of left ventricular contractility, while negative values indicate functional preservation or enhancement.
DISCUSSION
The present study demonstrates that MRS4719 exerts a nonlinear dose- and duration-dependent effect on post-stroke recovery, revealing a narrow therapeutic window for optimal P2X4R modulation. Our findings provide several important insights relevant to both mechanistic and translational application. First, we observed a non-linear dose-response relationship, in which an intermediate dose (2.25 mg/kg/day) maximally improved sensorimotor performance, while higher (3 mg/kg/day) doses were less effective. Although a lower dose (1.5 mg/kg/day) also preserved tissue integrity, similar to the intermediate dose, it did not consistently translate into functional improvement, whereas higher doses failed to provide histological protection. This dissociation underscores that structural preservation alone is insufficient to predict functional recovery and suggests that excessive P2X4R inhibition may disrupt the signaling pathways necessary for adaptive plasticity during long term recovery (2). To further interpret this nonlinear dose-response, it is important to consider the context-dependent dual role of P2X4R signaling. During the acute phase of ischemic injury, P2X4R activation amplifies ATP-driven inflammatory responses that exacerbate tissue damage, whereas in the subacute to chronic phase it contributes to reparative processes, including BDNF release and synaptic remodeling. Thus, excessive inhibition at higher doses (3 mg/kg/day) may suppress not only detrimental inflammatory signaling but also these adaptive recovery mechanisms, resulting in diminished overall efficacy. In contrast, intermediate dosing likely achieves a balanced modulation attenuating early injury while preserving later-stage repair pathways thereby producing optimal structural and functional outcomes. This framework provides a mechanistically grounded explanation for the observed inverted U-shaped dose-response and underscores the importance of precise titration of P2X4R inhibition. Second, treatment duration emerged as a critical determinant of long-term outcome. Short-term inhibition (2 days) was sufficient to confer sustained improvements in both sensorimotor and cognitive recovery without adverse effects, whereas prolonged treatment for 7 days did not enhance efficacy and increased inter-animal variability. Therefore, treatment duration and dose of the P2X4R antagonist is critical for optimal beneficial effects of MRS 4719. These findings are consistent with the dual role of P2X4R signaling—where early inhibition limits ATP-driven inflammatory injury, but prolonged suppression may interfere with later reparative processes such as BDNF-mediated synaptic remodeling (2).
Most importantly, we demonstrate that delayed initiation of MRS4719 treatment at 4–12 hrs. after ischemic onset remains effective in reducing infarct injury. This extended therapeutic window demonstrates that MRS4719 reduces infarct volume when administered up to 12 hrs. after stroke onset (Fig. 3), consistent with the possibility that P2X4R inhibition may affect injury mechanisms that evolve over time and can be translationally relevant. As post-ischemic ATP release, microglial activation, and inflammatory signaling persist well beyond the acute phase, delayed modulation of P2X4R activity may remain therapeutically effective. These findings highlight the translational potential of MRS4719 as a post-acute intervention capable of extending treatment opportunities to a broader stroke population and complementing existing reperfusion strategies. These data support a model in which precise temporal and quantitative inhibition of P2X4R during the early post-ischemic phase optimally balances neuroprotection and recovery. Based on integrated functional and histological outcomes, a dose of 2.25 mg/kg/day administered for two days may represent an optimal regimen for future mechanistic and translational studies in mice. These findings advance P2X4R inhibition as a rational, time-sensitive therapeutic strategy for improving cognitive and histological outcomes after ischemic stroke. The observation that MRS4719 is protective in both brain and heart underscores the shared molecular mechanisms driving ischemia/reperfusion injury across organ systems (13). In both settings, extracellular ATP released from damaged cells activates the P2X4R on resident and infiltrating immune cells, thus amplifying inflammatory responses that exacerbate tissue injury (2,10). By dampening this ATP–P2X4R axis, MRS4719 may reduce maladaptive inflammation while preserving functional recovery. Importantly, the beneficial effects observed in two distinct vital organs strengthen the translational potential of P2X4R inhibition as a systemic therapeutic strategy for ischemic diseases. Given the shared pathophysiology of ischemic injury across organ systems, P2X4R-mediated signaling may also contribute to kidney ischemia/reperfusion injury, suggesting that MRS4719 could have therapeutic potential in this context. Future work will be required to directly evaluate this possibility. Supporting this rationale, prior studies have shown that renal proximal tubular P2X4 activation exacerbates ischemic AKI and promotes NLRP3 inflammasome signaling (9) It should be noted that P2X4R activation in cardiomyocytes and endothelium generally promotes adaptive responses (enhanced cardiac function, NO-mediated vasodilation) that may mitigate I/R damage (11). However, the precise balance between acute injury vs. chronic remodeling is still unclear and our data with acute injury show a protective effect after its blockade. Notably, the dose selected for the cardiac I/R studies (2.0 mg/kg/day) falls within the effective range defined in our stroke experiments. Given the nonlinear dose-response observed, we prioritized testing a dose within this therapeutic window rather than a single “optimal” value to evaluate cross-organ efficacy. This approach minimizes the risk of overdosing while preserving biological activity and supports the concept that partial, rather than maximal, P2X4R inhibition may be sufficient to confer protection across different ischemic contexts.
These results are highly novel and translational as they determine precise dose-, duration-, and time-dependent effects, identifying a nonlinear dose-response and an optimal short-duration treatment paradigm for MRS4719 never reported earlier.
We also want to acknowledge some limitations of this work. 1) While the observed preservation of cardiac function following ischemia/reperfusion injury supports a protective role of P2X4R inhibition, this component of the study should be considered exploratory. The current analysis is limited to early echocardiographic outcomes and does not include infarct size quantification, histological assessment, or inflammatory profiling. Therefore, the cardiac findings primarily serve as proof-of-concept for a broader, cross-organ role of P2X4R signaling in ischemic injury. Future studies incorporating structural and molecular endpoints will be necessary to fully define the cardioprotective mechanisms and therapeutic potential of MRS4719. 2) Both male and female mice were included and evenly distributed across treatment groups (supplementary table 1); however, the study was not powered to detect sex-specific differences in treatment response. Therefore, potential sex-dependent effects of MRS4719 cannot be excluded and warrant systematic evaluation in future adequately powered studies. 3) Novel object recognition performance improved with short-term MRS4719 treatment, though the 2-day group showed greater inter-animal variability. The modest separation between sham and vehicle groups limits interpretability and suggests this cognitive measure is sensitive to biological and experimental variability. Accordingly, these findings should be interpreted cautiously and validated in larger cohorts to enhance statistical robustness and reproducibility
MATERIALS AND METHODS
All procedures were approved by the Institutional Animal Care and Use Committee (approved protocol no. AP-201043–0926 and AP-201036–1026) and conducted in accordance with NIH guidelines. Details of materials, methods, experimental design, behavioral procedure and other methods can be found in the supplementary file.
Statistical Analysis
Statistical analyses were performed using GraphPad Prism (version 10.3). Data distribution was assessed for normality prior to analysis. Comparisons between two groups were performed using unpaired two-tailed Student’s t-tests. For experiments involving more than two groups, one-way ANOVA followed by Tukey’s multiple comparisons test was used. Repeated behavioral measurements were analyzed using two-way ANOVA with appropriate post hoc testing, when applicable. Data are presented as mean ± standard deviation (SD). A p-value < 0.05 was considered statistically significant.
Supplementary Material
ACKNOWLEDGEMENTS
This research was supported by the Intramural Research Program (ZIADK31127) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services (to KAJ). This work was supported by NINDS grant 1R01NS125405–01A1 (to RV) and the Calhoun Cardiology Research Endowment and NIH grants HL48225 and HL152710 (to BTL).
Footnotes
Ethics declarations
Competing interests
Dr. Bruce T. Liang is consultant in Provascore, and the other authors declare no competing interests.
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