Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
Department of Legal Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada-cho, Kahoku-gun, Ishikawa, 920-0293, Japan.
Sci Rep. 2020 Feb 13;10(1):2602. doi: 10.1038/s41598-020-59377-6.
Oxidative stress has been suggested to play a role in brain damage during carbon monoxide (CO) poisoning. Severe poisoning induced by CO at 3000 ppm, but not 1000 ppm, enhances hydroxyl radical (˙OH) production in the rat striatum, which might be mediated by NADPH oxidase (NOX) activation associated with Ras-related C3 botulinum toxin substrate (Rac) via cAMP signaling pathway activation. CO-induced ˙OH production was suppressed by antagonists of angiotensin II (AngII) type 1 receptor (AT1R) and type 2 receptor (AT2R) but not an antagonist of the Mas receptor. Suppression by an AT1R antagonist was unrelated to peroxisome proliferator-activated receptor γ. Angiotensin-converting enzyme inhibitors also suppressed CO-induced ˙OH production. Intrastriatal AngII at high concentrations enhanced ˙OH production. However, the enhancement of ˙OH production was resistant to inhibitors selective for NOX and Rac and to AT1R and AT2R antagonists. This indicates a different mechanism for ˙OH production induced by AngII than for that induced by CO poisoning. AT1R and AT2R antagonists had no significant effects on CO-induced cAMP production or ˙OH production induced by forskolin, which stimulates cAMP production. These findings suggest that the renin-angiotensin system might be involved in CO-induced ˙OH production in a manner independent of cAMP signaling pathways.
氧化应激被认为在一氧化碳（CO）中毒导致的脑损伤中发挥作用。3000ppm 而非 1000ppm 的 CO 重度中毒会增强大鼠纹状体中羟自由基（˙OH）的产生，这可能是通过 cAMP 信号通路激活与 Ras 相关 C3 肉毒杆菌毒素底物（Rac）相关的 NADPH 氧化酶（NOX）激活介导的。CO 诱导的˙OH 产生被血管紧张素 II（AngII）1 型受体（AT1R）和 2 型受体（AT2R）拮抗剂抑制，但 Mas 受体拮抗剂则无抑制作用。AT1R 拮抗剂的抑制作用与过氧化物酶体增殖物激活受体γ无关。血管紧张素转化酶抑制剂也抑制 CO 诱导的˙OH 产生。纹状体内高浓度的 AngII 增强了˙OH 的产生。然而，这种˙OH 产生的增强对选择性 NOX 和 Rac 抑制剂以及 AT1R 和 AT2R 拮抗剂具有抗性。这表明 AngII 诱导的˙OH 产生与 CO 中毒诱导的˙OH 产生的机制不同。AT1R 和 AT2R 拮抗剂对 CO 诱导的 cAMP 产生或 forskolin（刺激 cAMP 产生）诱导的˙OH 产生没有显著影响。这些发现表明，肾素-血管紧张素系统可能以独立于 cAMP 信号通路的方式参与 CO 诱导的˙OH 产生。
