C–Glucosyl Xanthone derivative Mangiferin downregulates the JNK3 mediated caspase activation in Almal induced neurotoxicity in differentiated SHSY-5Y neuroblastoma cells

Abstract

Introduction

C-Glucosyl Xanthone derivatives were assessed to inhibit the JNK3 mediated Caspase pathway in Almal (Aluminum Maltolate) induced neurotoxicity in SHSY-5Y cells.

Methods

Mangiferin was selected among 200 C-Glucosyl Xanthones based on molecular interaction, docking score (−10.22 kcal/mol), binding free energy (−71.12 kcal/mol), ADME/tox properties and by molecular dynamic studies. Further, it was noticed that glycone moiety of Mangiferin forms H-bond with ASN 194, SER 193, GLY 76, and OH group in the first position of the aglycone moiety shows interaction at Met 149 which is exceptionally crucial for JNK3 inhibitory activity.

Results and discussion

Mangiferin (0.5, 1, 10, 20 and 30 µM) and standard SP600125 (20 µM) treatment increased the cell survival rate against Almal 200 µM, with EC50 of Mangiferin (8 µM) and standard SP600125 (4.9 µM) respectively. Mangiferin significantly impedes kinase activation, indicating suppression of JNK3 signaling with IC50 (98.26 nM). Mangiferin (10 and 15 µM) dose-dependently inhibits the caspase 3, 8, and 9 enzyme activation in comparison to Almal group.

Conclusion

Mangiferin demonstrated neuroprotection in SHSY-5Y cells against apoptosis induced by Almal by adapting the architecture of the neurons and increasing their density. Among all Xanthone derivatives, Mangiferin could improve neuronal toxicity by inhibiting JNK3 and down-regulating the Caspase activation.

Keywords:

• C–glucosyl xanthones
• mangiferin
• Al-Maltolate
• JNK3
• caspase enzymes
• SHSY-5Y neuroblastoma cells
• neurotoxicity

Acknowledgments

We would like to acknowledge PSG College of Pharmacy for letting us access all of its materials and equipment.

Ethics statement

The experimental protocols were approved by the institutional human ethics committee of PSGIMS&R/18/085.

Authors’ contributions

Ms. Nafila. PK contributed proposal writing and study follow-up, Ravi Kumar Rajan contributed In Vitro study part, Vanitha Nanchappan contributed study monitoring, sample processing and manuscript writing, Arjunan Karuppaiah contributed analytical part of the study, Jaikanth Chandrasekaran contributed Insilco part, Saravanan Jayaraman contributed pathological sample processing, Venkatesh Gunasekaran contributed study design, study monitoring, final manuscript draft preparation and communication.

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

The essential details will be disclosed upon request.

Additional information

Funding

This research is not supported any funding agencies.