NTRK1-mediated protection against manganese-induced neurotoxicity and cell apoptosis via IGF2 in SH-SY5Y cells

  • Biomed Pharmacother. 2023 Nov 18:169:115889. doi: 10.1016/j.biopha.2023.115889.
Caixia Zhang  1 ,  Bo Jiao  1 ,  Xueqin Cao  1 ,  Wencui Zhang  1 ,  Shangchen Yu  1 ,  Kaiwen Zhang  1 ,  Mi Zhang  2 ,  Xianwei Zhang  3
Affiliations
  • 1. Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
  • 2. Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China. Electronic address: [email protected].
  • 3. Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China. Electronic address: [email protected].
PMID: 37984302 DOI: 10.1016/j.biopha.2023.115889
Abstract

Background: Excessive manganese (Mn) exposure has been linked to neurotoxicity, cognitive impairments. Neurotrophic Receptor Kinase 1 (NTRK1) encodes Tropomyosin kinase A (TrkA), a neurotrophic receptor, as a mediator of neuron differentiation and survival. Insulin-like growth factor 2 (IGF2), a pivotal member of the Insulin gene family, plays a crucial role in brain development and neuroprotection. Despite this knowledge, the precise mechanisms through which NTRK1 and IGF2 influence cell responses to Mn-induced neuronal damage remain elusive.

Methods: Cell Apoptosis was assessed using CCK8, TUNEL staining, and Western blot analysis of cleaved Caspase-3. Lentiviral vectors facilitated NTRK1 overexpression, while small interfering RNAs (siRNAs) facilitated IGF2 knockdown. Real-time Quantitative PCR (qPCR) determined gene expression levels, while Western blotting measured protein expression.

Results: The study reveals that NTRK1 inhibits MnCl2-induced Apoptosis in SH-SY5Y cells. NTRK1 overexpression significantly upregulated IGF2 expression, and subsequent siRNA-IGF2 experiments confirmed IGF2's pivotal role in NTRK1-mediated neuroprotection. Notably, the study identifies that NTRK1 regulates the expression of IGF2 in the neuroprotective mechanism with the involvement of ER stress pathways.

Discussion: The study reveals NTRK1's neuroprotective role via IGF2 against Mn-induced neurotoxicity and ER stress modulation in SH-SY5Y cells. These findings offer insights into potential therapies for neurodegenerative disorders related to Mn exposure and NTRK1 dysfunction, driving future research in this domain.

Keywords
Apoptosis; ER stress; IGF2; MnCl2; NTRK1; SH-SY5Y cell.
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