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Research Article | 28 Jun 2026

Melatonin attenuates fluoride-induced neurotoxicity and cognitive dysfunction through modulation of oxidative stress, neuroinflammation, and SIRT1 signaling in Wistar rats

Newly Bagang1, Nitesh Kumar2, Somasish Ghosh Dastidar3, Anoop Kishore4, K. G. Mohandas Rao5, G. Sivakumar6, and Smita Shenoy1 Show more
VETERINARY WORLD | Article No. 28 | pg no. 2650-2666 | Vol. 19, Issue 6 | DOI: 10.14202/vetworld.2026.2650-2666
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ABSTRACT

                      
Background and Aim: Chronic fluoride exposure causes neurotoxicity, oxidative stress, neuroinflammation, and cognitive impairment, posing a significant public health concern. This study investigated the neuroprotective potential of melatonin against fluoride-induced neurotoxicity and cognitive dysfunction in male and female Wistar rats, with emphasis on oxidative stress, neuroinflammation, apoptosis, and sirtuin 1 (SIRT1) signaling. 
Materials and Methods: Four-week-old Wistar albino rats (n=8 per group per sex) were exposed to sodium fluoride (NaF, 50 ppm in drinking water) alone or co-treated with melatonin (10 or 20 mg/kg, oral) for 8 weeks. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition Test (NORT). Serum fluoride, brain SIRT1, oxidative stress markers (malondialdehyde [MDA], superoxide dismutase [SOD]), apoptosis markers (caspase-3, B-cell lymphoma 2 [Bcl-2]), inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]), acetylcholinesterase (AChE) levels, and hippocampal histopathology were evaluated. 
Results: NaF exposure significantly elevated serum fluoride, reduced brain SIRT1, increased oxidative stress, apoptosis, neuroinflammation, AChE activity, and caused hippocampal neuronal damage, leading to impaired learning and memory in both sexes (p < 0.05). Melatonin co-treatment (both doses) significantly attenuated these changes by lowering serum fluoride, restoring SIRT1 levels, reducing MDA, caspase-3, TNF-α, IL-6, and AChE, while increasing SOD and Bcl-2. It also improved behavioral performance in the MWM and NORT and preserved hippocampal neuronal morphology. Effects were comparable between sexes and between the two melatonin doses. 
Conclusion: Melatonin effectively mitigates fluoride-induced neurotoxicity and cognitive dysfunction in Wistar rats by modulating oxidative stress, neuroinflammation, apoptosis, and SIRT1 signaling. These findings highlight melatonin as a promising neuroprotective agent against environmental fluoride toxicity, with potential translational relevance for fluorosis-endemic areas. 
                      
Keywords: cognitive dysfunction, fluoride neurotoxicity, melatonin, neuroinflammation, neuroprotection, oxidative stress, SIRT1, Wistar rats.