Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH

• DOI: 10.1161/strokeaha.123.043005
• Publication Date: 2023-07-19T09:08:52Z
• Authors: Xionghui Chen; Xuying He; Feng Xu; Ningbo Xu; Nona Hashem Sharifi; Pengjie Zhang; Jerry J. Flores; Lei Wu; Qiuguang He; Hideki Kanamaru; Shiyi Zhu; Siyuan Dong; Mingyang Han; Ye Yuan; Lei Huang; Liyan Miao; John H. Zhang; Youxin Zhou; Jiping Tang
• Keywords: CX3CR1

Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated gamma) pathway after experimental germinal matrix hemorrhage (GMH).A total 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase stereotactically guided infusion. administered intranasally at 1, 25, 49 hours short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, foot-fault test) performed 24 to 28 days with treatment once daily days. To elucidate mechanism, CRISPR, or selective inhibitor AZD8797, intracerebroventricularly preinduction GMH. Selective inhibition AMPK/PPARγ signaling in microglia via delivery liposome-encapsulated specific (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl Hemoglobin assay, ELISA assay performed.The brain expression FKN elevated expressed both neurons microglia, whereas mainly Intranasal administration improved short- long-term deficits promoted M2 polarization, thereby attenuating neuroinflammation enhancing clearance, which accompanied an increased ratio p-AMPK (phosphorylation AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related 2), PPARγ, CD36 (cluster differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose IL (interleukin)-10 expression, decreased CD68 68), IL-1β, TNF (tumor necrosis factor) α expression. The CRISPR (AZD8797) abolished protective effect FKN. Furthermore, microglial abrogated anti-inflammation effects GMH.CX3CR1 attenuated partially through pathway, M1/M2 polarization. Activating may provide promising approach treating patients