Inja Cho1,2, Jeong Min Kim1,2, Eun Jung Kim1,2, So Yeon Kim1,2, Eun Hee Kam1,2, Eunji Cheong3, Minah Suh4,5,6,7, Bon-Nyeo Koo8,9. 1. Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. 2. Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea. 3. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. 4. Department of Biomedical Engineering, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeong gi-do, 16419, Republic of Korea. 5. Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Sungkyunkwan University, Suwon, Korea. 6. Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, South Korea. 7. Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Suwon, 16419, South Korea. 8. Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. koobn@yuhs.ac. 9. Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea. koobn@yuhs.ac.
Abstract
BACKGROUND: Postoperative pain is a common phenomenon after surgery and is closely associated with the development of postoperative cognitive dysfunction (POCD). Persistent pain and systemic inflammation caused by surgery have been suggested as key factors for the development of POCD. Fractalkine (CX3CL1) and its receptor, the CX3C chemokine receptor 1 (CX3CR1), are known to play a key role in pain and inflammation signaling pathways. Recent studies have shown that the regulation of CX3CR1/L1 signaling influences the development of various diseases including neuronal diseases. We determined whether CX3CR1/L1 signaling is a putative therapeutic target for POCD in a mouse model. METHODS: Adult (9-11 weeks) male mice were treated with neutralizing antibody to block CX3CR1/L1 signaling both before and after surgery. Inflammatory and behavioral responses including pain were assessed postoperatively. Also, CX3CR1 mRNA level was assessed. Hippocampal astrocyte activation, Mao B expression, and GABA expression were assessed at 2 days after surgery following neutralizing antibody administration. RESULTS: The behavioral response indicated cognitive dysfunction and development of pain in the surgery group compared with the control group. Also, increased levels of pro-inflammatory cytokines and CX3CR1 mRNA were observed in the surgery group. In addition, increased levels of GABA and increased Mao B expression were observed in reactive astrocytes in the surgery group; these responses were attenuated by neutralizing antibody administration. CONCLUSIONS: Increased CX3CR1 after surgery is both necessary and sufficient to induce cognitive dysfunction. CX3CR1 could be an important target for therapeutic strategies to prevent the development of POCD.
BACKGROUND:Postoperative pain is a common phenomenon after surgery and is closely associated with the development of postoperative cognitive dysfunction (POCD). Persistent pain and systemic inflammation caused by surgery have been suggested as key factors for the development of POCD. Fractalkine (CX3CL1) and its receptor, the CX3C chemokine receptor 1 (CX3CR1), are known to play a key role in pain and inflammation signaling pathways. Recent studies have shown that the regulation of CX3CR1/L1 signaling influences the development of various diseases including neuronal diseases. We determined whether CX3CR1/L1 signaling is a putative therapeutic target for POCD in a mouse model. METHODS: Adult (9-11 weeks) male mice were treated with neutralizing antibody to block CX3CR1/L1 signaling both before and after surgery. Inflammatory and behavioral responses including pain were assessed postoperatively. Also, CX3CR1 mRNA level was assessed. Hippocampal astrocyte activation, Mao B expression, and GABA expression were assessed at 2 days after surgery following neutralizing antibody administration. RESULTS: The behavioral response indicated cognitive dysfunction and development of pain in the surgery group compared with the control group. Also, increased levels of pro-inflammatory cytokines and CX3CR1 mRNA were observed in the surgery group. In addition, increased levels of GABA and increased Mao B expression were observed in reactive astrocytes in the surgery group; these responses were attenuated by neutralizing antibody administration. CONCLUSIONS: Increased CX3CR1 after surgery is both necessary and sufficient to induce cognitive dysfunction. CX3CR1 could be an important target for therapeutic strategies to prevent the development of POCD.
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