Possible Involvement of Cellular Pathway and Cytokines in Manganese Induced Neurotoxicity in Neuroblastoma Cells via KH–Type Splicing Regulatory Protein

Abstract

Pharmacognosy Research,2023,15,2,307-314.DOI:10.5530/pres.15.2.033Published:February 2023Type:Original Article Authors:Sharad Singh, Sunil More, G. S. Latha, Himanshu Agrawal, Veena S M, and Francois Niyonzima Author(s) affiliations:Sharad Singh1, Sunil More1,*, G. S. Latha2, Himanshu Agrawal3, Veena S M4, Francois Niyonzima5 1School of Basic and Applied Sciences, Dayananada Sagar University, Bangalore, Karnataka, INDIA. 2Department of Physiology, Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, A Constituent College under Dr. M.G.R. Educational and Research Institute, Chennai, Tamil Nadu, INDIA. 3Jubilant Biosys Limited, Bangalore, Karnataka, INDIA. 4Department of Biotechnology, Sapthagiri College of Engineering, Bengaluru, Karnataka, INDIA. 5Department of Mathematics, Sciences and Physical Education, University of Rwanda-College of Education (UR-CE), Kayonza Rukara Campus, RWANDA. Abstract:Background: Manganese is a toxic essential trace element and too high concentration instigates the neurodegenerative disease known as parkinsonism. Effects of manganese may lead to apoptosis. However, a detailed mechanism of manganese toxicity has not been fully elucidated. Previous published articles have highlighted the augmentation of KHSRP expression following Mn exposure. Objectives: In this work, the importance of KHSRP in Mn–induced toxicity was checked along with the impact of other known neurotoxicity inhibitors on KHSRP. Materials and Methods: KHSRP expression, pro and anti-inflammatory cytokines, chemokines, and pharmacological inhibitors (SAHA, Quercetin, and MCC950) were determined by exposing N2a cells to various MnCl2 concentrations. ANOVA and Dunnett’s test were used to decide on the significance. Results: MnCl2 treatment led to the augmentation of the KHSPR mRNA expression and protein increase in N2a cell line. The MnCl2 treatment of N2a cells also showed an elevated liberation of IL-6, TNF-α, MCP–1, and IL-1β. Pharmacological agents like quercetin inhibiting PI3K, MAPK, and WNT pathways, MCC950 blocking NLRP3 pathways, and SAHA showed a decrease in KHSRP expression post Mn treatment. With the inhibition of KHSRP, a decline in the release of IL-1β, IL-6, MCP–1, and TNF-α was also observed. Conclusion: These results suggested that MnCl2 treatment of N2a cells induce the expression of KHSRP via the PI3K–or NLRP3 pathway. Furthermore, this elevated expression of KHSRP is responsible for an increment in the liberation of pro-inflammatory markers in N2a cells. More exploration is needed to throw light on the pathway driving the KHSRP. Keywords:KH–type Splicing Regulatory Protein, Manganese Neurotoxicity, Neuroblastoma, Neurodegeneration, Neuroinflammation.View:PDF (1.26 MB)