1b638bba40dcf3bc790d43547b8e08d3 antioxidants-15-01080-v2.pdf ba294abb10ef2f7f7cf2c8ab7e137eec44ec5ea1 antioxidants-15-01080-v2.pdf fc7de96e08c4d3dae490725271ccb5b852b499da94976c0efa531c60adf83309 antioxidants-15-01080-v2.pdf Title: Dimethyl Fumarate and Cobalt Protoporphyrin IX Inhibit Fibromyalgia-like Pain by Modulating Region-Specific Redox Pathways Subject: Fibromyalgia is a chronic nociplastic pain disorder characterized by widespread pain and affective disturbances, in which oxidative stress and neuroinflammation are now recognized as central pathogenic mechanisms. However, current therapies provide only limited symptomatic relief. This study compared the therapeutic and molecular effects of dimethyl fumarate (DMF), an activator of nuclear factor erythroid 2-related factor 2 (NRF2), and cobalt protoporphyrin IX (CoPP), an inducer of heme oxygenase-1 (HO-1), in a reserpine-induced mouse model of fibromyalgia-like pain. Male and female C57BL/6J mice received repeated reserpine administration to induce mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors. Therapeutic efficacy was evaluated by behavioral testing and molecular analyses of the periaqueductal gray (PAG), anterior cingulate cortex (ACC), and spinal cord (SC). DMF produced a faster antinociceptive response than CoPP, although both compounds ultimately reversed nociceptive hypersensitivity and depressive-like behaviors in male and female mice. These behavioral alterations were associated with increased NLRP3 expression and activated AKT signaling, together with region-specific redox dysregulation involving differential regulation of NADPH oxidases and endogenous antioxidant defenses. Both treatments differentially modulated region-specific redox alterations, enhanced selected antioxidant defenses, and attenuated inflammatory and nociception-related signaling. These findings identify region-specific redox dysregulation as a prominent feature of fibromyalgia-like pathology, providing new mechanistic insight into the molecular basis of nociplastic pain. Collectively, these results demonstrate that DMF and CoPP treatments remodel region-specific redox networks while inhibiting both sensory and affective manifestations of fibromyalgia-like pain, supporting endogenous antioxidant pathways as promising mechanism-based therapeutic targets for fibromyalgia. Keywords: fibromyalgia; nociplastic pain; dimethyl fumarate; cobalt protoporphyrin IX; NRF2; HO-1; oxidative stress; NLRP3 inflammasome; depression; neuroplasticity Author: Sylmara Esther Negrini-Ferrari, Weitao Wang and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Aug 31 09:34:35 2026 CEST ModDate: Mon Aug 31 09:42:02 2026 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 24 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 7385497 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OXLAQS+URWPalladioL-Ital Type 1 Custom yes yes yes 125 0 PPOMGS+URWPalladioL-Bold Type 1 Custom yes yes yes 126 0 LRHRCY+VnURWPalladioL Type 1 Custom yes yes yes 127 0 ZWVWFY+URWPalladioL-Roma Type 1 Custom yes yes yes 128 0 TDUDTH+CMSY10 Type 1 Builtin yes yes yes 180 0 VVSYYB+EURM10 Type 1 Builtin yes yes yes 181 0 TVHGTW+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 290 0 MVTLZK+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 291 0 YVQFLM+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 292 0 MVTLZK+PalatinoLinotype-Roman TrueType WinAnsi yes yes yes 386 0 TVHGTW+PalatinoLinotype-Bold TrueType WinAnsi yes yes yes 387 0 YVQFLM+PalatinoLinotype-Italic TrueType WinAnsi yes yes yes 388 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-10-02 04:05:11 CEST RepresentationInformation: antioxidants-15-01080-v2.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-10-01 05:20:47 CEST Size: 7385497 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 648 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Materials and Methods Children: Item: Title: Animals Item: Title: Establishment of a Fibromyalgia-like Condition Item: Title: Assessment of Nociceptive Responses Item: Title: Assessment of Depressive-like Behaviors Item: Title: Drugs Item: Title: Experimental Protocol Item: Title: Protein Expression Analysis by Western Blot Item: Title: Statistical Evaluation Item: Title: Results Children: Item: Title: DMF and CoPP Reverse Reserpine-Induced Nociceptive Hypersensitivity in Male and Female Mice Item: Title: DMF and CoPP Reverse Reserpine-Induced Depressive-like Behaviors in Male and Female Mice Item: Title: DMF and CoPP Differentially Modulate Inflammatory and Redox-Related Proteins in the PAG Item: Title: DMF and CoPP Elicit a Selective Molecular Response in the ACC Item: Title: DMF and CoPP Differentially Modulate Inflammatory and Redox Signaling in the SC Item: Title: Discussion Item: Title: Conclusions Item: Title: References Info: Title: Dimethyl Fumarate and Cobalt Protoporphyrin IX Inhibit Fibromyalgia-like Pain by Modulating Region-Specific Redox Pathways Author: Sylmara Esther Negrini-Ferrari, Weitao Wang and Olga Pol Subject: Fibromyalgia is a chronic nociplastic pain disorder characterized by widespread pain and affective disturbances, in which oxidative stress and neuroinflammation are now recognized as central pathogenic mechanisms. However, current therapies provide only limited symptomatic relief. This study compared the therapeutic and molecular effects of dimethyl fumarate (DMF), an activator of nuclear factor erythroid 2-related factor 2 (NRF2), and cobalt protoporphyrin IX (CoPP), an inducer of heme oxygenase-1 (HO-1), in a reserpine-induced mouse model of fibromyalgia-like pain. Male and female C57BL/6J mice received repeated reserpine administration to induce mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors. Therapeutic efficacy was evaluated by behavioral testing and molecular analyses of the periaqueductal gray (PAG), anterior cingulate cortex (ACC), and spinal cord (SC). DMF produced a faster antinociceptive response than CoPP, although both compounds ultimately reversed nociceptive hypersensitivity and depressive-like behaviors in male and female mice. These behavioral alterations were associated with increased NLRP3 expression and activated AKT signaling, together with region-specific redox dysregulation involving differential regulation of NADPH oxidases and endogenous antioxidant defenses. Both treatments differentially modulated region-specific redox alterations, enhanced selected antioxidant defenses, and attenuated inflammatory and nociception-related signaling. These findings identify region-specific redox dysregulation as a prominent feature of fibromyalgia-like pathology, providing new mechanistic insight into the molecular basis of nociplastic pain. Collectively, these results demonstrate that DMF and CoPP treatments remodel region-specific redox networks while inhibiting both sensory and affective manifestations of fibromyalgia-like pain, supporting endogenous antioxidant pathways as promising mechanism-based therapeutic targets for fibromyalgia. 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