The inhibitory effect of gadolinium-conjugated diflunisal on platelet function through regulating outside-in signaling of αIIbβ3 integrin
- 1Korean Medicine-Application Center, Korea Institute of Oriental Medicine
- 2Korean Convergence Medical Science Major, KIOM School, University of Science and Technology (UST)
- 3Department of R & D Center, Etnova Therapeutics Corp.
Abstract
The gadolinium-conjugated diflunisal derivative ETN102 has previously been shown to suppress cyclooxygenase-2 (COX-2) levels, reduce glial activation, and attenuate neuronal damage associated with stroke. In the present study, we investigated whether ETN102 modulates platelet aggregation and activation. ETN102 selectively inhibited thrombin-induced platelet aggregation while sparing platelet responses to other agonists, including collagen, adenosine diphosphate (ADP), and U46619. ETN102 also reduced adenosine triphosphate (ATP) secretion under aggregating conditions without altering thromboxane B ₂ (TXB ₂ ) generation, suggesting that its antiplatelet effect is independent of the COX-1-dependent thromboxane signaling. Flow cytometric and biochemical analyses further demonstrated that ETN102 suppressed thrombin-induced αIIbβ3 integrin activation, platelet spreading, clot retraction, and the phosphorylation of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), without affecting granule secretion, intracellular Ca ²⁺ mobilization, or phosphorylation of Syk, PI3K, and AKT signaling molecules. In vivo , ETN102 significantly prolonged carotid artery occlusion time in a ferric chloride (FeCl ₃ )-induced thrombosis model and increased tail bleeding time and hemoglobin content. In addition, ETN102 reduced infarct volume and improved neuronal survival markers in a murine model of cerebral ischemia/reperfusion injury. These findings demonstrate that ETN102 is a thrombin-context selective modulator of platelet integrin αIIbβ3 outside-in signaling, with antithrombotic and neuroprotective potential.
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BibTeX
@article{pak2026inhibitory,
title = {{The inhibitory effect of gadolinium-conjugated diflunisal on platelet function through regulating outside-in signaling of αIIbβ3 integrin}},
author = {Malk Eun Pak and Yeon-Ji Kim and Hado Choi and Garam Choi and Yeoun-Hee Kim and Kyungho Kim},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1936307},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1936307/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The inhibitory effect of gadolinium-conjugated diflunisal on platelet function through regulating outside-in signaling of αIIbβ3 integrin
AU - Malk Eun Pak
AU - Yeon-Ji Kim
AU - Hado Choi
AU - Garam Choi
AU - Yeoun-Hee Kim
AU - Kyungho Kim
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1936307
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1936307/full
AB - The gadolinium-conjugated diflunisal derivative ETN102 has previously been shown to suppress cyclooxygenase-2 (COX-2) levels, reduce glial activation, and attenuate neuronal damage associated with stroke. In the present study, we investigated whether ETN102 modulates platelet aggregation and activation. ETN102 selectively inhibited thrombin-induced platelet aggregation while sparing platelet responses to other agonists, including collagen, adenosine diphosphate (ADP), and U46619. ETN102 also reduced adenosine triphosphate (ATP) secretion under aggregating conditions without altering thromboxane B ₂ (TXB ₂ ) generation, suggesting that its antiplatelet effect is independent of the COX-1-dependent thromboxane signaling. Flow cytometric and biochemical analyses further demonstrated that ETN102 suppressed thrombin-induced αIIbβ3 integrin activation, platelet spreading, clot retraction, and the phosphorylation of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), without affecting granule secretion, intracellular Ca ²⁺ mobilization, or phosphorylation of Syk, PI3K, and AKT signaling molecules. In vivo , ETN102 significantly prolonged carotid artery occlusion time in a ferric chloride (FeCl ₃ )-induced thrombosis model and increased tail bleeding time and hemoglobin content. In addition, ETN102 reduced infarct volume and improved neuronal survival markers in a murine model of cerebral ischemia/reperfusion injury. These findings demonstrate that ETN102 is a thrombin-context selective modulator of platelet integrin αIIbβ3 outside-in signaling, with antithrombotic and neuroprotective potential.
SN - 1663-9812
ER -