title: Ozone (O3) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing ER Ca(2+) release and activating the CaMKII/MAPK signaling pathway.
abstract: Ozone (O3) is widely used in the treatment of spinal cord related diseases. Excess or accumulation of this photochemical air can however be neurotoxic. In this study, in vitro cultured Wister rat spinal cord neurons (SCNs) were used to investigate the detrimental effects and underlying mechanisms of O3. Ozone in a dose-dependent manner inhibited cell viability at a range of 20 to 500 μg/ml, with the dose at 40 μg/ml resulting in a decrease of cell viability to 75%. The cell death after O3 exposure was related to endoplasmic reticulum (ER) calcium (Ca(2+)) release. Intracellular Ca(2+) chelator, ER stabilizer (inositol 1,4,5-trisphosphate receptor (IP3R) antagonist and ryanodine receptor (RyR) antagonist) and calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist could effectively block Ca(2+) mobilization and inhibit cell death following 40 μg/ml O3 exposure. In addition, ER Ca(2+) release due to O3 exposure enhanced phospho-p38 and phospho-JNK levels and apoptosis of SCNs through activating CaMKII. Based on these results, we confirm that ozone elicits neurotoxicity in SCNs via inducing ER Ca(2+) release and activating CaMKII/MAPK signaling pathway. Therefore, physicians should get attention to the selection of treatment concentrations of oxygen/ozone. And, approaches, such as chelating intracellular Ca(2+) and stabilizing neuronal Ca(2+) homeostasis could effectively ameliorate the neurotoxicity of O3.
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: XueJun
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: Juntian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: Wang
authors.initials: W
authors.lastname: JunNan
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong Province 250021, China. Electronic address: zhijian_fu@163.com.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*; D010126:Ozone / Q000378:metabolism* / Q000633:toxicity; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*
chemical_list: D001896:Boron Compounds; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D010126:Ozone; C109986:2-aminoethoxydiphenyl borate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003620:Dantrolene
keywords: CaMKII; Endoplasmic reticulum (ER) calcium (Ca(2+)) Release; MAPK pathway; Neurotoxicity; Ozone