ccaa2be7dec6920cdaa042146e9924d2 antioxidants-14-01004-v2.pdf 082b8acfaf196869e14093f033feb27c6c679958 antioxidants-14-01004-v2.pdf 69b6d8ef068c9dfa83d61131b28e214485692b74fa4fb611326877e20da6a1b1 antioxidants-14-01004-v2.pdf Title: Preventing Cisplatin-Induced Neuropathy and Related Emotional Disorders with the Coadministration of Duloxetine and Hydrogen-Rich Water in Male and Female Mice Subject: Cisplatin (CIS)-induced peripheral neuropathy and associated comorbidities have a detrimental effect on the lives of cancer patients. Currently, there are no effective therapies to alleviate these symptoms. Duloxetine (DULO) is a recommended treatment, but it is linked with important side effects, thus making it essential to explore novel approaches. We examined the impact of a prophylactic treatment with a low dose of DULO combined with hydrogen-rich water (HRW) on CIS-injected C57BL/6 male and female mice as a possible therapy for allodynia, muscle and body weight deficits, and emotive syndromes accompanying this type of chemotherapy. The prophylactic treatment with DULO and HRW prevented mechanical allodynia caused by CIS in both sexes and had greater effects than either treatment given individually. The combined treatment also prevented cold allodynia in male mice but only reduced it in females. Moreover, the coadministration of DULO with HRW avoided muscular deficits in both sexes. Furthermore, the body weight reduction induced by CIS in both sexes was not entirely mitigated by the combined therapy. However, all treatments avoided the anxiety- and depressive-like behaviors elicited by CIS. The antiallodynic actions and prevention of muscular deficits produced by the combined treatment might be explained by the inhibition of oxidative stress, inflammatory responses, and plasticity alterations provoked by CIS in the dorsal root ganglia of these subjects. This study proposes, for the first time, the cotreatment of DULO with HRW as an effective therapy for CIS-induced peripheral neuropathy and reveals the influence of sex on these actions. Keywords: anxiety; chemotherapy-induced peripheral neuropathy; cisplatin; depression; duloxetine; hydrogen-rich water; inflammation; molecular hydrogen; oxidative stress Author: Ignacio Martínez-Martel, Sylmara Esther Negrini-Ferrari and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Aug 18 14:13:21 2025 CEST ModDate: Mon Aug 18 14:40:53 2025 CEST Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 30 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 7378643 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- PEXOHB+URWPalladioL-Roma Type 1 Custom yes yes yes 120 0 QKZKVH+VnURWPalladioL Type 1 Custom yes yes yes 121 0 OUPKXO+URWPalladioL-Ital Type 1 Custom yes yes yes 122 0 PPJNLP+URWPalladioL-Bold Type 1 Custom yes 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yes 1526 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-09-05 03:08:35 CEST RepresentationInformation: antioxidants-14-01004-v2.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-09-04 06:06:12 CEST Size: 7378643 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1582 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: Experimental Design Item: Title: Administration of Drugs Item: Title: Allodynia Item: Title: Grip Strength Test Item: Title: Anxiety- and Depressive-like Comportments Item: Title: Western Blot Item: Title: Statistical Analyses Item: Title: Results Children: Item: Title: The Impact of Sex on the Mechanical and Cold Allodynia and the Grip Strength and Body Weight Loss Caused by CIS in Mice Item: Title: The Effects of DULO Combined with HRW on the Mechanical and Cold Allodynia and the Grip Strength and Weight Loss Instigated by CIS in Male and Female Mice Item: Title: Treatment with DULO and HRW Alone and Combined Avoided the Development of Emotional Disorders Associated with CIS-Induced Chemotherapy Item: Title: The Impact of Treatment with DULO and HRW Alone and Combined on the Oxidative Stress, Inflammatory Responses, and Plasticity Changes Triggered by CIS in the DRG and AMG of Male and Female Mice Item: Title: Discussion Item: Title: Conclusions Item: Title: References Info: Title: Preventing Cisplatin-Induced Neuropathy and Related Emotional Disorders with the Coadministration of Duloxetine and Hydrogen-Rich Water in Male and Female Mice Author: Ignacio Martínez-Martel, Sylmara Esther Negrini-Ferrari and Olga Pol Subject: Cisplatin (CIS)-induced peripheral neuropathy and associated comorbidities have a detrimental effect on the lives of cancer patients. Currently, there are no effective therapies to alleviate these symptoms. Duloxetine (DULO) is a recommended treatment, but it is linked with important side effects, thus making it essential to explore novel approaches. We examined the impact of a prophylactic treatment with a low dose of DULO combined with hydrogen-rich water (HRW) on CIS-injected C57BL/6 male and female mice as a possible therapy for allodynia, muscle and body weight deficits, and emotive syndromes accompanying this type of chemotherapy. The prophylactic treatment with DULO and HRW prevented mechanical allodynia caused by CIS in both sexes and had greater effects than either treatment given individually. The combined treatment also prevented cold allodynia in male mice but only reduced it in females. Moreover, the coadministration of DULO with HRW avoided muscular deficits in both sexes. Furthermore, the body weight reduction induced by CIS in both sexes was not entirely mitigated by the combined therapy. However, all treatments avoided the anxiety- and depressive-like behaviors elicited by CIS. The antiallodynic actions and prevention of muscular deficits produced by the combined treatment might be explained by the inhibition of oxidative stress, inflammatory responses, and plasticity alterations provoked by CIS in the dorsal root ganglia of these subjects. This study proposes, for the first time, the cotreatment of DULO with HRW as an effective therapy for CIS-induced peripheral neuropathy and reveals the influence of sex on these actions. 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