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Naringin alleviates fluoride-induced neurodevelopmental disorders by modulation of SIRT1, autophagy, mitochondrial fission, and ROS generation.
| Naunyn-Schmiedeberg's Archives of Pharmacology | Chhabra V, Swamy RS, Reddy ART, Bhushan R, Shenoy S, Maiti S, Abubakar, Meenakshi S, Murti K, Kumar N. |
Autophagy Mitochondrial dynamics Neurogenesis SIRT1 Neurodevelopmental Oxidative Stress Animal Study

Abstract

The present study explored the mechanism behind the fluorosis-mediated neurodevelopmental disorder and its intervention by naringin in prenatal and perinatal models in Wistar rats. Both in vitro and in vivo studies were conducted to assess autophagy, oxidative stress, neurogenesis, and impaired molecular dynamics markers. The experiment was conducted over a period of 120 days. Twelve Wistar rats were divided into four groups: control, sodium fluoride (NaF)-treated (10 ppm in drinking water), NaF + naringin-treated (50 mg/kg via oral gavage), and NaF with naringin administered to pups via breastfeeding. Treatments lasted 60 days for adults, with NaF exposure beginning 30 days pre-mating. Pups were evaluated at days 90 (prenatal) and 120 (perinatal) to assess developmental effects. Fluoride was administered by mixing NaF in drinking water at a dose of 10 ppm, and naringin was given via oral gavage at a dose of 50 mg/kg body weight. Fluoride toxicity showed altered behavior in the open field test (OFT), novel object recognition test (NORT), forced swim test (FST), and Morris Water Maze tests and impaired motor coordination in neonatal tests using nest seeking, locomotion, righting reflex, forelimb grasp reflex, cliff avoidance, and negative geotactic reflex. At the end of the experiment, prenatal and natal pups were sacrificed postweaning. Biochemical assays, fluoride concentration estimation, Western blotting, and immunohistochemistry were performed for the brain tissues. Naringin showed improvement in these behavioral studies, probably due to neuroprotection by modulation of SIRT-1, Dnm1L, and Lc3B levels, which were assessed by western blot. These findings highlight naringin as a promising therapeutic agent for mitigating fluoride-induced neurodevelopmental toxicity through pathways involving oxidative stress regulation, autophagy, and mitochondrial dynamics.

Data availability

All source data for this work (or generated in this study) are available upon reasonable request.

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Acknowledgements

We thank the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Government of India for providing stipends and infrastructural support to Vishal Chhabra, Annem Ravi Teja Reddy, Rashmi Bhushan, Md Abubakar and Sarasa Meenakshi. We also thank the Indian Council of Medical Research, New Delhi for providing funding support and fellowship to Shreya Maity.

Funding

We thank ICMR for providing extramural funding for the project (Grant Number 5/8–4/6/Env/2020-NCD-II), P.I. Dr. Nitesh Kumar, Co-PI: Ravindra Shantakumar Swamy and Smita Shenoy.

Author information

Author notes

  1. Vishal Chhabra and Ravindra Shantakumar Swamy contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India

    Vishal Chhabra, Rashmi Bhushan, Shreya Maiti,  Abubakar & Nitesh Kumar

  2. Division of Anatomy, Department of Basic Medical Sciences (DBMS), Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India

    Ravindra Shantakumar Swamy

  3. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India

    Annem Ravi Teja Reddy

  4. Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India

    Smita Shenoy

  5. Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Hajipur, Vaishali, Bihar, 844102, India

    Sarasa Meenakshi & Krishna Murti

Contributions

Design of study and reviewing the original draft: Ravindra Shantakumar Swamy, Smita Shenoy, Krishna Murti, Nitesh Kumar. In vivo study, In vitro study, Data interpretation and writing manuscript: Vishal Chhabra, Ravindra Shantakumar Swami, Annem Ravi Teja Reddy, Rashmi Bhushan, Shreya Maiti, Md Abubakar, Sarasa Meenakshi. All authors reviewed the final draft manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Nitesh Kumar.

Ethics declarations

Competing interests

The authors declare no competing interests.

ABSTRACT ONLINE AT https://link.springer.com/article/10.1007/s00210-025-04398-z