2,5-Hexanedione Induced Apoptosis in Rat Spinal Cord Neurons and VSC4.1 Cells Via the ProNGF/p75NTR and JNK Pathways

Overview

Journal Biosci Rep

Specialty Cell Biology

Date 2021 Apr 1

PMID 33792642

Citations 5

Authors

Mengxin Luo

Xiaoxia Shi

Qi Guo

Shuangyue Li

Qing Zhang

Xiuyan Sun

Fengyuan Piao

Affiliations

Soon will be listed here.

Abstract

Increasing evidence suggests that n-hexane induces nerve injury via neuronal apoptosis induced by its active metabolite 2,5-hexanedione (HD). However, the underlying mechanism remains unknown. Studies have confirmed that pro-nerve growth factor (proNGF), a precursor of mature nerve growth factor (mNGF), might activate apoptotic signaling by binding to p75 neurotrophin receptor (p75NTR) in neurons. Therefore, we studied the mechanism of the proNGF/p75NTR pathway in HD-induced neuronal apoptosis. Sprague-Dawley (SD) rats were injected with 400 mg/kg HD once a day for 5 weeks, and VSC4.1 cells were treated with 10, 20, and 40 mM HD in vitro. Results showed that HD effectively induced neuronal apoptosis. Moreover, it up-regulated proNGF and p75NTR levels, activated c-Jun N-terminal kinase (JNK) and c-Jun, and disrupted the balance between B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Our findings revealed that the proNGF/p75NTR signaling pathway was involved in HD-induced neuronal apoptosis; it can serve as a theoretical basis for further exploration of the neurotoxic mechanisms of HD.

Citing Articles

Investigating the Interplay Between the Nrf2/Keap1/HO-1/SIRT-1 Pathway and the p75NTR/PI3K/Akt/MAPK Cascade in Neurological Disorders: Mechanistic Insights and Therapeutic Innovations.

Mukherjee R, Rana R, Mehan S, Khan Z, Gupta G, Narula A Mol Neurobiol. 2025; .

PMID: 39920438 DOI: 10.1007/s12035-025-04725-8.

Elucidation of the effects of 2,5-hexandione as a metabolite of -hexane on cognitive impairment in leptin-knockout mice (C57BL/6-Lepem1Shwl/Korl).

Nguyen H, Jo W, Cha J, Hoang N, Kim M Toxicol Res. 2024; 40(3):389-408.

PMID: 38911537 PMC: 11187033. DOI: 10.1007/s43188-024-00228-1.

Exposure to volatile hydrocarbons and neurologic function among oil spill workers up to 6 years after the Deepwater Horizon disaster.

Chen D, Werder E, Stewart P, Stenzel M, Gerr F, Lawrence K Environ Res. 2023; 231(Pt 1):116069.

PMID: 37149022 PMC: 10330421. DOI: 10.1016/j.envres.2023.116069.

miR-6315 silencing protects against spinal cord injury through the Smo and anti-ferroptosis pathway.

Ma Z, Fan Y, Peng Y, Bian L, Zhou J, Wang L Biosci Rep. 2023; 43(4).

PMID: 36946310 PMC: 10086115. DOI: 10.1042/BSR20230030.

Towards Substitution of Hexane as Extraction Solvent of Food Products and Ingredients with No Regrets.

Cravotto C, Fabiano-Tixier A, Claux O, Abert-Vian M, Tabasso S, Cravotto G Foods. 2022; 11(21).

PMID: 36360023 PMC: 9655691. DOI: 10.3390/foods11213412.

References

Herskowitz A, Ishii N, Schaumburg H . N-hexane neuropathy. A syndrome occurring as a result of industrial exposure. N Engl J Med. 1971; 285(2):82-5. DOI: 10.1056/NEJM197107082850204. View

Allard S, Leon W, Pakavathkumar P, Bruno M, Ribeiro-da-Silva A, Cuello A . Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype. J Neurosci. 2012; 32(6):2002-12. PMC: 6621687. DOI: 10.1523/JNEUROSCI.1144-11.2012. View

Li F, Huang Y, Zou H, Xu Q, Hu Y, Zhang M . An outbreak of -hexane poisoning associated with employer's lack of legal awareness at a family-run clothing workshop. Clin Toxicol (Phila). 2020; 58(11):1072-1073. DOI: 10.1080/15563650.2020.1733000. View

Popova D, Karlsson J, Jacobsson S . Comparison of neurons derived from mouse P19, rat PC12 and human SH-SY5Y cells in the assessment of chemical- and toxin-induced neurotoxicity. BMC Pharmacol Toxicol. 2017; 18(1):42. PMC: 5460426. DOI: 10.1186/s40360-017-0151-8. View

Ledesma M, Abad-Rodriguez J, Galvan C, Biondi E, Navarro P, Delacourte A . Raft disorganization leads to reduced plasmin activity in Alzheimer's disease brains. EMBO Rep. 2003; 4(12):1190-6. PMC: 1326416. DOI: 10.1038/sj.embor.7400021. View

Lehning E, Jortner B, Fox J, Arezzo J, Kitano T, Lopachin R . gamma-diketone peripheral neuropathy. I. Quality morphometric analyses of axonal atrophy and swelling. Toxicol Appl Pharmacol. 2000; 165(2):127-40. DOI: 10.1006/taap.2000.8937. View

Spencer P, Schaumburg H . Ultrastructural studies of the dying-back process. III. The evolution of experimental peripheral giant axonal degeneration. J Neuropathol Exp Neurol. 1977; 36(2):276-99. DOI: 10.1097/00005072-197703000-00005. View

Piao F, Chen Y, Yu L, Shi X, Liu X, Jiang L . 2,5-hexanedione-induced deregulation of axon-related microRNA expression in rat nerve tissues. Toxicol Lett. 2019; 320:95-102. DOI: 10.1016/j.toxlet.2019.11.019. View

Ogawa Y, Shimizu H, Kim S . 2,5-Hexanedione induced apoptosis in cultured mouse DRG neurons. Int Arch Occup Environ Health. 1996; 68(6):495-7. DOI: 10.1007/BF00377875. View

10.

Provenzano M, Xu N, Ver Meer M, Clark J, Hansen M . p75NTR and sortilin increase after facial nerve injury. Laryngoscope. 2007; 118(1):87-93. DOI: 10.1097/MLG.0b013e31814b8d9f. View

11.

Zhao R, Yu Q, Hou L, Dong X, Zhang H, Chen X . Cadmium induces mitochondrial ROS inactivation of XIAP pathway leading to apoptosis in neuronal cells. Int J Biochem Cell Biol. 2020; 121:105715. PMC: 7045337. DOI: 10.1016/j.biocel.2020.105715. View

12.

Teng H, Teng K, Lee R, Wright S, Tevar S, Almeida R . ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005; 25(22):5455-63. PMC: 6724992. DOI: 10.1523/JNEUROSCI.5123-04.2005. View

13.

Lebrun-Julien F, Bertrand M, De Backer O, Stellwagen D, Morales C, Di Polo A . ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci U S A. 2010; 107(8):3817-22. PMC: 2840442. DOI: 10.1073/pnas.0909276107. View

14.

Wang Z, Qiu Z, Gao C, Sun Y, Dong W, Zhang Y . 2,5-hexanedione downregulates nerve growth factor and induces neuron apoptosis in the spinal cord of rats via inhibition of the PI3K/Akt signaling pathway. PLoS One. 2017; 12(6):e0179388. PMC: 5487034. DOI: 10.1371/journal.pone.0179388. View

15.

Melchor J, Pawlak R, Strickland S . The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J Neurosci. 2003; 23(26):8867-71. PMC: 6740393. View

16.

Shanab A, Mysona B, Matragoon S, El-Remessy A . Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. Mol Ther Methods Clin Dev. 2015; 2:15013. PMC: 4445004. DOI: 10.1038/mtm.2015.13. View

17.

Fuchs Y, Steller H . Programmed cell death in animal development and disease. Cell. 2011; 147(4):742-58. PMC: 4511103. DOI: 10.1016/j.cell.2011.10.033. View

18.

Iulita M, Do Carmo S, Ower A, Fortress A, Aguilar L, Hanna M . Nerve growth factor metabolic dysfunction in Down's syndrome brains. Brain. 2014; 137(Pt 3):860-72. PMC: 3927704. DOI: 10.1093/brain/awt372. View

19.

Li S, Qi Y, Hu S, Piao F, Guan H, Wang Z . Mesenchymal stem cells-conditioned medium protects PC12 cells against 2,5-hexanedione-induced apoptosis via inhibiting mitochondria-dependent caspase 3 pathway. Toxicol Ind Health. 2015; 33(2):107-118. DOI: 10.1177/0748233715598267. View

20.

Wang B, Gao Y, Xiao Z, Chen B, Han J, Zhang J . Erk1/2 promotes proliferation and inhibits neuronal differentiation of neural stem cells. Neurosci Lett. 2009; 461(3):252-7. DOI: 10.1016/j.neulet.2009.06.020. View