Naringenin, a dietary flavanone, enhances insulin-like growth factor 1 receptor-mediated antioxidant defense and attenuates methylglyoxal-induced neurite damage and apoptotic death

ABSTRACT

Objectives: Recent studies revealed the neuroprotective effects of naringenin (NGEN), a common dietary bioflavonoid contained in citrus fruits. However, there are limited data on its protection against methylglyoxal (MG), the most potent precursor of advanced glycation end-products. The present study was to investigate the protection of NGEN on MG-induced neurotoxicity and the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling.

Methods: NSC34 motor neuron-like cells was used. Cell viability was measured by MTT assay. Protein expressions were analyzed by western blots. Morphological changes of neurites were observed by an inverted microscope. Reactive oxygen species (ROS) production and apoptotic cell numbers were measured by flow cytometer. Glutathione (GSH) level and superoxide dismutase (SOD) activity were measured by ELISA.

Results: >NGEN attenuated ROS production and increased GSH level, SOD activity and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear expression in MG-treated NSC34 cells. NGEN also increased neurite length and enhanced IGF-1R and p-Akt in MG-treated NSC34 cells. Furthermore, NGEN attenuated MG-induced apoptotic death accompanied with down-regulation of cleaved-poly (ADP-ribose) polymerase (PARP) and up-regulation of B-cell lymphoma-2 (Bcl-2). However, AG1024, an IGF-1R antagonist, attenuated the anti-oxidative and anti-apoptotic effects of NGEN in MG-treated cells.

Discussion: The present results demonstrated that NGEN decreased neuronal apoptosis and improved antioxidant defense in MG-treated NSC34 cells. Moreover, IGF-1R-mediated antioxidant defense plays an important role in this protective mechanism. These findings suggest the potential benefits of NGEN on the prevention of MG-induced or diabetes/hyperglycemia-related neurotoxicity. In vivo studies are needed for further confirmation on NGEN-mediated neuroprotection.

KEYWORDS:

• Naringenin
• insulin-like growth factor 1
• methylglyoxal
• glucose neurotoxicity
• antioxidant defense
• anti-apoptosis
• motor neurons

Acknowledgements

Y. C. Lo, Y. T. Tseng and H. T. Hsu designed the study; Y. T. Tseng, T. Y. Lee and W. H. Chang performed the experiments and analyzed the data; Y. C. Lo, Y. T. Tseng and H. T. Hsu wrote this paper; Y. C. Lo and H. T. Hsu contributed essential reagents and tools.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Yu-Ting Tseng is a Ph.D. in pharmaceutical science and worked as a post-doctoral research fellow in Department of Pharmacology at Kaohsiung Medicine University since 2016 and was previously assisted in many research projects at the Department during her Ph.D. Her research interests focus on drug development on neurodegenerative diseases, muscle atrophy, and inflammation- and oxidative stress-related diseases, evaluation of pharmacological mechanisms, and herbal medicine and natural products.

Hung-Te Hsu is currently a Director of Anesthesiology at Kaohsiung Municipal Ta-Tung Hospital and an Assistant Professor of Anesthesiology at Kaohsiung Medical University. He holds a M.D. Ph.D. degree in medicine. Dr. Hsu has expertise in anesthesia of thoracic surgery, ultrasound-guided nerve block, and advanced management of upper respiratory tract.

Tzu-Ying Lee is currently a post-doctoral fellow at the Department of Pharmacology, Kaohsiung Medical University. She received her Masters and Ph.D. degrees from the College of Medicine Kaohsiung Medical University in 2005 and 2015 respectively. In her doctoral thesis, she mainly studied the liver toxicity of silver nanoparticles in rats. Dr. Lee's other prior works involved the correlation between microRNA and colorectal cancer resistance and the use of mitochondrial transfer to aid in the treatment of sepsis.

Wan-Hsuan Chang is currently a research assistant at the Department of Pharmacology, Kaohsiung Medicine University. She received a Master degree in Science from Department of Biological Sciences at National Sun Yat-Sen University. Her research interests include Acinetobacter baumanii-caused lung injury and Formosan fragrance compositions development on neuroprotection.

Yi-Ching Lo is currently a Professor of Pharmacology at College of Medicine, Kaohsiung Medicine University. Her research expertise is in the areas of multi-target drugs discovery for neurodegenerative diseases, muscular atrophy and mental diseases. Specifically, her current research focuses on the development of drugs with neuroprotective or muscular protein enhancing benefits, including chemical compounds, natural products, herb medicine and traditional Chinese medicine. She has established several cellular and animal disease models of neurodegeneration and skeletal muscle atrophy caused by inflammation, oxidative stress, aging and metabolic diseases, providing platforms for new drug development.

Additional information

Funding

This work was supported by Ministry of Science and Technology of Taiwan under grant [MOST 105-2320-B-037-013-MY3] to Y. C. Lo.; and Kaohsiung Medical University under grant [kmtth-103-021] to H. T. Hsu.