225c7902cda9eac46d26952e3e5de5db antioxidants-14-00143.pdf 722c0538c76fc7ac203f645d97cf0a47eb80cbb1 antioxidants-14-00143.pdf a74c5d9eae303ee0717d8baa9349aabe30951a9fac87ae02dae65bfa056ccf77 antioxidants-14-00143.pdf Title: MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice Subject: Chemotherapy-induced peripheral neuropathy and the accompanying affective disorders are serious side effects, and their resolution is not guaranteed. Oxidative stress and elevated levels of Nod-like receptor protein 3 (NLRP3) have been detected in the peripheral and central nervous systems of animals with neuropathic pain provoked by several antineoplastic drugs, such as paclitaxel (PTX). Several studies have further indicated that NLRP3 inflammasome inhibition could be an approach for treating chronic pain, but its impact on the anxiodepressive-like behaviors and memory deficits related to PTX-provoked neuropathy has not yet been investigated. MCC950 is a potent and specific inhibitor of the NLRP3 pathway that acts through inhibiting NLRP3 activation and inflammasome formation. We hypothesized that the administration of MCC950 could alleviate the affective and cognitive disorders accompanying PTX-provoked neuropathy. Using male C57BL/6 mice, we assessed the effects of MCC950 on the mechanical and thermal allodynia, anxiodepressive-like behavior, and memory deficits incited by this taxane. The results indicated that the intraperitoneal administration of 10 mg/kg of MCC950 twice daily for three consecutive days fully reversed the PTX-induced mechanical and thermal allodynia. This treatment also completely attenuated the anxiolytic (p < 0.004) and depressive-like behaviors (p < 0.022) and memory deficits (novel object recognition test; p < 0.0018) incited by PTX. These actions were mainly achieved through blocking NLRP3 inflammasome activation in the sciatic nerve, amygdala, and hippocampus, and oxidative stress in the amygdala and hippocampus. MCC950 also normalized the p-ERK 1/2 overexpression in the sciatic nerve and apoptotic responses in the sciatic nerve and the amygdala. This study suggests that MCC950 might be a promising treatment for PTX-induced mental illnesses and neuropathy. Keywords: anxiety; depression; MCC950; memory; neuropathic pain; NLRP3 inflammasome; oxidative stress; paclitaxel Author: Ignacio Martínez-Martel, Sylmara Esther Negrini-Ferrari and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sat Jan 25 08:35:52 2025 CET ModDate: Sat Jan 25 08:38:35 2025 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4545088 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AIRHKL+VnURWPalladioL Type 1 Custom yes yes yes 10 0 UNPDRB+URWPalladioL-Roma Type 1 Custom yes yes yes 16 0 NEJUTF+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 QUKGTP+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 JDWIZJ+EURM10 Type 1 Builtin yes yes yes 53 0 QMDDXF+CMSY10 Type 1 Builtin yes 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(2023-03-16) LastModified: 2025-02-12 07:37:44 CET Size: 4545088 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 618 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Animals Destination: subsection.2.1 Item: Title: Experimental Procedures Destination: subsection.2.2 Item: Title: PTX Injection Destination: subsection.2.3 Item: Title: Drugs Destination: subsection.2.4 Item: Title: Allodynia Tests Destination: subsection.2.5 Item: Title: Emotional Behavior Tests Destination: subsection.2.6 Item: Title: Cognitive Behavior Test Destination: subsection.2.7 Item: Title: Western Blot Analysis Destination: subsection.2.8 Item: Title: Statistical Analyses Destination: subsection.2.9 Item: Title: Results Destination: section.3 Children: Item: Title: The Effects of MCC950 on the Mechanical and Thermal Allodynia Caused by PTX Destination: subsection.3.1 Item: Title: The Effects of MCC950 on the Anxiodepressive-like Behaviors and Memory Loss Linked to PTX Destination: subsection.3.2 Item: Title: The Effects of MCC950 on the Inflammatory, Oxidative, Plasticity, and Apoptotic Changes Provoked by PTX in the Sciatic Nerve, Amygdala, and Hippocampus Destination: subsection.3.3 Item: Title: The Effects of HRW on the Antiallodynic Actions of MCC950 in PTX-Injected Mice Destination: subsection.3.4 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.6 Info: Title: MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice Author: Ignacio Martínez-Martel, Sylmara Esther Negrini-Ferrari and Olga Pol Subject: Chemotherapy-induced peripheral neuropathy and the accompanying affective disorders are serious side effects, and their resolution is not guaranteed. Oxidative stress and elevated levels of Nod-like receptor protein 3 (NLRP3) have been detected in the peripheral and central nervous systems of animals with neuropathic pain provoked by several antineoplastic drugs, such as paclitaxel (PTX). Several studies have further indicated that NLRP3 inflammasome inhibition could be an approach for treating chronic pain, but its impact on the anxiodepressive-like behaviors and memory deficits related to PTX-provoked neuropathy has not yet been investigated. MCC950 is a potent and specific inhibitor of the NLRP3 pathway that acts through inhibiting NLRP3 activation and inflammasome formation. We hypothesized that the administration of MCC950 could alleviate the affective and cognitive disorders accompanying PTX-provoked neuropathy. Using male C57BL/6 mice, we assessed the effects of MCC950 on the mechanical and thermal allodynia, anxiodepressive-like behavior, and memory deficits incited by this taxane. The results indicated that the intraperitoneal administration of 10 mg/kg of MCC950 twice daily for three consecutive days fully reversed the PTX-induced mechanical and thermal allodynia. This treatment also completely attenuated the anxiolytic (p < 0.004) and depressive-like behaviors (p < 0.022) and memory deficits (novel object recognition test; p < 0.0018) incited by PTX. These actions were mainly achieved through blocking NLRP3 inflammasome activation in the sciatic nerve, amygdala, and hippocampus, and oxidative stress in the amygdala and hippocampus. MCC950 also normalized the p-ERK 1/2 overexpression in the sciatic nerve and apoptotic responses in the sciatic nerve and the amygdala. This study suggests that MCC950 might be a promising treatment for PTX-induced mental illnesses and neuropathy. 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