Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect in patients receiving anticancer treatments including Paclitaxel (PTX) and Vincristine (VCR), and can lead to chronic pain and worsening quality of life. In severe neuropathy, chemotherapy dose reduction or withdrawal can occur, with possible impairment of oncological outcome. The lack of effective therapy is partly due to an incomplete knowledge of CIPN pathogenesis. Emerging studies suggest a possible role for neuroinflammation in CIPN. Methods: We evaluated the inflammatory response in two preclinical models. Female Wistar rats were treated intravenously with PTX at dosages of 10 mg/Kg 1qwx4, while VCR were injected with 0.2 mg/kg 1qwx4. Multimodal assessment of CIPN was performed (neurophysiology and behavioral tests) periodically during treatment and neuroinflammatory markers in dorsal root ganglia (DRG) and spinal cord were investigated. Results: PTX and VCR- treated rats showed allodynia and neurophysiological alterations, with reduction in intraepidermic nervous fiber (IENF) density, but showed different severity of axonopathy in peripheral nerves. With PTX, peripheral nerves initially showed increased M1-macrophages infiltration, with subsequent glial fibrillary acid protein (GFAP) upregulation in DRG satellite cells and spinal astrocytes. Conversely, VCR showed no significant macrophage infiltration in peripheral nerves, but induced a positive microglial reaction for ionized calcium-binding adapter molecule 1 (Iba1) in the spinal cord, suggesting involvement in the maintenance phase of persistent pain state. Conclusions Our findings suggest the need for targeting different neuroinflammatory pathways to restore or relieve neuropathic phenotypes and indicate the need for better understanding of the roles of peripheral and central glial cells in relationship with CIPN. This work is supported by Fondazione Cariplo, Grant #2019-1482
Meregalli, C., Chiorazzi, A., Argentini, A., Ballarini, E., Canta, A., Carozzi, V., et al. (2024). Insight Into Chemotherapeutic-Agents-Induced-Neuroinflammation In Rat Experimental Neuropathies. In 2024 PNS Annual Meeting – Montreal Canada, 22-25 June 2024 (pp.179-179). WILEY [10.1111/jns.12648].
Insight Into Chemotherapeutic-Agents-Induced-Neuroinflammation In Rat Experimental Neuropathies
Meregalli ,CPrimo
;Chiorazzi, A;Argentini, A;Ballarini, Elisa;Canta, A;Carozzi V;Malacrida, A;Marmiroli, P;Tarasiuk, O;Cavaletti, GUltimo
2024
Abstract
Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect in patients receiving anticancer treatments including Paclitaxel (PTX) and Vincristine (VCR), and can lead to chronic pain and worsening quality of life. In severe neuropathy, chemotherapy dose reduction or withdrawal can occur, with possible impairment of oncological outcome. The lack of effective therapy is partly due to an incomplete knowledge of CIPN pathogenesis. Emerging studies suggest a possible role for neuroinflammation in CIPN. Methods: We evaluated the inflammatory response in two preclinical models. Female Wistar rats were treated intravenously with PTX at dosages of 10 mg/Kg 1qwx4, while VCR were injected with 0.2 mg/kg 1qwx4. Multimodal assessment of CIPN was performed (neurophysiology and behavioral tests) periodically during treatment and neuroinflammatory markers in dorsal root ganglia (DRG) and spinal cord were investigated. Results: PTX and VCR- treated rats showed allodynia and neurophysiological alterations, with reduction in intraepidermic nervous fiber (IENF) density, but showed different severity of axonopathy in peripheral nerves. With PTX, peripheral nerves initially showed increased M1-macrophages infiltration, with subsequent glial fibrillary acid protein (GFAP) upregulation in DRG satellite cells and spinal astrocytes. Conversely, VCR showed no significant macrophage infiltration in peripheral nerves, but induced a positive microglial reaction for ionized calcium-binding adapter molecule 1 (Iba1) in the spinal cord, suggesting involvement in the maintenance phase of persistent pain state. Conclusions Our findings suggest the need for targeting different neuroinflammatory pathways to restore or relieve neuropathic phenotypes and indicate the need for better understanding of the roles of peripheral and central glial cells in relationship with CIPN. This work is supported by Fondazione Cariplo, Grant #2019-1482
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