Different mechanisms of hydroxyl radical production susceptible to purine P2 receptor antagonists between carbon monoxide poisoning and exogenous ATP in rat striatum
Different mechanisms of hydroxyl radical production susceptible to purine P2 receptor antagonists between carbon monoxide poisoning and exogenous ATP in rat striatum
复制标题
DOI：
10.3109/10715762.2014.951842
复制
发表时间：
2014-11-01
影响因子：
3.3
通讯作者：
Mizukami, H.
中科院分区：
文献类型：
--
作者：
Hara, S.;Kobayashi, M.;Mizukami, H.
先前的研究表明，一氧化碳（CO）中毒刺激cAMP的产生通过嘌呤P2 Y11样受体在大鼠纹状体，激活cAMP信号通路，导致羟基自由基（（OH）-O-中心点）的生产。细胞外ATP被认为可能触发级联反应，但本研究未能证明由于CO中毒导致的细胞外ATP的明显增加。CO诱导的（OH）-O-中心点的产生被P2 Y11受体拮抗剂NF 157减弱，与其抑制CO诱导的cAMP产生的能力平行。非选择性P2受体拮抗剂PPADS对cAMP的产生无影响，但对（OH）-O-中心点的产生有更强的抑制作用。对PPADS敏感的相应P2受体的选择性更强的拮抗剂，包括NF 279，对CO诱导的（OH）-O-中心点的产生几乎没有影响。纹状体内给予外源性ATP剂量依赖性地刺激（OH）-O-中心点的产生，PPADS和NF 279剂量依赖性地拮抗（OH）-O-中心点的产生，但NF 157不拮抗。外源性GTP和CTP剂量依赖性地刺激（OH）-O-中心点的产生，但效力较低。GTP诱导的（OH）-O-中心点的产生对NF 279和PPADS均敏感，而CTP诱导的（OH）-O-中心点的产生对PPADS具有抗性。CO中毒和外源性ATP引起的（OH）-O-中心点的产生机制可能不同，但多种P2受体可能参与了（OH）-O-中心点的产生。CO诱导的（OH）-O-中心点的产生对NADPH氧化酶的抑制敏感，但对黄嘌呤氧化酶的抑制不敏感。此外，NADPH氧化酶抑制抑制（OH）-O-中心点的生产所诱导的毛喉素，细胞内cAMP的形成刺激。推测CO中毒时NADPH氧化酶通过cAMP信号通路激活产生（OH）-O-中心点。
Previous studies have suggested that carbon monoxide (CO) poisoning stimulates cAMP production via purine P2Y11-like receptors in the rat striatum, activating cAMP signaling pathways, resulting in hydroxyl radical ((OH)-O-center dot) production. Extracellular ATP was thought likely to trigger the cascade, but the present study has failed to demonstrate a clear increase in the extracellular ATP due to CO poisoning. The CO-induced (OH)-O-center dot production was attenuated by the P2Y11 receptor antagonist NF157, in parallel with its abilities to suppress the CO-induced cAMP production. The (OH)-O-center dot production was more strongly suppressed by a non-selective P2 receptor antagonist, PPADS, which had no effect on cAMP production. More selective antagonists toward the respective P2 receptors susceptible to PPADS, including NF279, had little or no effect on the CO-induced (OH)-O-center dot production. The intrastriatal administration of exogenous ATP dose-dependently stimulated (OH)-O-center dot production, which was dose-dependently antagonized by PPADS and NF279 but not by NF157. Exogenous GTP and CTP dose-dependently stimulated (OH)-O-center dot production, though less potently. The GTP-induced (OH)-O-center dot production was susceptible to both of NF279 and PPADS, but the CTP-induced (OH)-O-center dot production was resistant to PPADS. The mechanism of (OH)-O-center dot production may differ between CO poisoning and exogenous ATP, while multiple P2 receptors could participate in (OH)-O-center dot production. The CO-induced (OH)-O-center dot production was susceptible to the inhibition of NADPH oxidase, but not xanthine oxidase. Also, the NADPH oxidase inhibition suppressed (OH)-O-center dot production induced by forskolin, a stimulator of intracellular cAMP formation. It is likely that (OH)-O-center dot is produced by NADPH oxidase activation via cAMP signaling pathways during CO poisoning.