Ozone (O3) elicits neurotoxicity in spinal cord neurons (SCNs) by inducing ER Ca2+ release and activating the CaMKII/MAPK signaling pathway

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 500μg/ml, with the dose at 40μg/ml resulting in a decrease of cell viability to 75%. The cell death after O3 exposure was related to endoplasmic reticulum (ER) calcium (Ca2+) release. Intracellular Ca2+ 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 Ca2+ mobilization and inhibit cell death following 40μg/ml O3 exposure. In addition, ER Ca2+ 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 Ca2+ 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 Ca2+ and stabilizing neuronal Ca2+ homeostasis could effectively ameliorate the neurotoxicity of O3. •Exposure to O3 can reduce the viability of SCNs and cause the cell death.•Exposure to O3 can trigger RyR and IP3R dependent intracellular Ca2+ release.•Exposure to O3 can enhance the phospho-CaMKII, phospho-JNK and phospho-p38 levels.