Potential Role of Zn Supplementation in Ameliorating Reserpine-Induced Fibromyalgia Manifestations Through Central NLRP3–Autophagy-Redox Network Modulation in Rats

Fibromyalgia is a chronic disorder of hyperalgesia and fatigue among other debilitating manifestations. Current antidepressant-based therapy is hampered by suboptimal tolerability. The main pathomechanism is central sensitization that is largely precipitated by glial neuroinflammation involving NLRP3 inflammasome pathway. Administration of Zn, a relatively tolerable and accessible mineral with established antioxidant and autophagy-promoting properties, was shown effective against fatigue syndromes and NLRP3 inflammasome activation, yet its effect on fibromyalgia remains elusive. The current study investigated the ameliorative efficacy of Zn administration against reserpine-induced fibromyalgia in rats. Sprague-Dawley male rats were randomized into four groups: normal control, reserpine (1 mg/kg, S.C.)-induced fibromyalgia model, and two groups receiving Zn gluconate (30 mg/kg, I.P.) daily either for a week post-induction or for a week pre- and post-induction. Zn administration alleviated reserpine-induced thermal allodynia (P < 0.0001), fatigue, and depression, but not weight loss or reduced food intake. Moreover, Zn reversed reserpine-mediated central neurodegeneration, glial activation (P < 0.01), and NLRP3 inflammasome upregulation as evidenced by significant decline in NF-κB/NLRP3/GSDMD/IL-1β and IL-18 axis with NLRP3 protein level at P < 0.01. Connectedly, Zn showed marked antioxidant and pro-autophagic effects through attenuating reserpine-induced MDA elevation (P < 0.05), total antioxidant capacity decline, Nrf2/HO-1 axis downregulation, and LC3-II: p62 balance reduction (P < 0.001). Post-treatment conferred superior histological protection, while pre-and-post-treatment provided better behavioral outcomes, NLRP3 expression decline, and redox improvements. In conclusion, this study suggests a potential role of Zn supplementation in amelioration of and protection against FM manifestations through controlling central NLRP3-autophagy-oxidative stress network, yet the potentially context- and exposure-dependent effects of Zn warrant further investigations.

Graphical Abstract

Reserpine-Induced FM Rat Model: Zn Supplementation Post-/Pre-and-Post-Induction Alleviated Central Sensitization through Glial NLRP3-Autophagy-Redox Modulation. GSDMD: Gasdermin D, GSDMD-N: Gasdermin D (N-terminal), HO-1: Heme Oxygenase 1, IκB: Inhibitor Protein of NF-κB, IL: Interleukin, NF-κB: Nuclear Factor kappa-B, NLRP3: Nucleotide-Binding Domain-, Leucine-Rich Repeat-, and Pyrin Domain-Containing Protein 3, Nrf2: Nuclear Factor Erythroid 2-Related Factor, ROS: Reactive Oxygen Species, ZnPO: Zn Gluconate Post-Treatment group, ZnPP: Zn Gluconate Pre- and Post-Treatment group. Servier Medical Art by Servier (nucleus, and protein icons; licensed under CC BY 3.0); NIAID Visual and Medical Arts (icons of inflammasome components, DNA; bioart.niaid.nih.gov); Database Center for Life Science (DBCLS) (interneuron icon; licensed under CC BY 4.0). Specific contributions from the Bio Nitro and Bioicons platforms include icons by Qara (NLRP3 complex), jaiganesh (mitochondria), and Rahel-Khdhr (ROS icon; licensed under CC BY SA 4.0). The rat illustration was generated through Google Gemini Nano Banana 2 Lite (Google, CA, USA) before manual marking of the cerebral cortex and lumbar spinal cord regions. Figure created using Inkscape v1.4.3 software (https://inkscape.org)