Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury
Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury
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DOI：
10.1089/089771502320317113
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发表时间：
2002-08-01
影响因子：
4.2
通讯作者：
Armstead, WM
中科院分区：
文献类型：
--
作者：
Kulkarni, M;Armstead, WM
先前的研究观察到，最近描述的内源性阿片类药物，伤害感受肽/孤啡肽FQ（NOC/oFQ），通过环氧合酶（COX）依赖性超氧阴离子（O-2（-））的生成，导致流体冲击脑损伤（FPI）后N-甲基-D-天冬氨酸（NMDA）诱导的脑血管舒张受损。本研究旨在研究颅窗关闭的仔猪 FPI 后 NMDA 扩张受损时 NOC/oFQ（另一种阿片类药物强啡肽）与酶 COX-2 亚型激活之间的关系。超氧化物歧化酶（SOD）抑制硝基蓝四唑（NBT）的还原被确定为O-2（-）生成的指标。在非脑损伤条件下，NOC/oFQ (10(-10) M)（FPI 后观察到的 CSF 浓度）增加了 CSF 强啡肽，而 NOC/oFQ 拮抗剂 [F/G] NOC/oFQ (1-13) NH2 减弱了 FPI 后强啡肽的刺激释放（34 +/- 3 和 97 +/- 6 vs. 36 +/- 3 和 68） +/- 8 在未治疗和 NOC/oFQ 拮抗剂预处理的动物中，FPI 前后 CSF 强啡肽的浓度为 pg/mol）。 FPI 增加了 SOD 抑制性 NBT 的减少，但用强啡肽拮抗剂去甲托菲明或 COX-2 抑制剂 NS398 进行预处理，减弱了这种减少（对照为 1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2)，FPI、FPI-去甲托菲明和 分别为 FPI-NS398）。在非脑损伤条件下，FPI 后在 CSF 中观察到的强啡肽浓度也会增加 SOD 抑制的 NBT 减少，但 NS398 会减弱这种减少。 NMDA 诱导的软脑膜动脉扩张在 FPI 后逆转为血管收缩，但用降巴哪托菲明或 NS398 预处理部分保护了这种反应（9 +/- 1 和 16 +/- 1，对照；-8 +/- 1 和 -13 +/- 2，FPI；6 +/- 1 和 12 +/- 1% FPI-降巴那托菲明用于 NMDA 分别为 10(-8)、10(-6) M)。这些数据表明，NOC/oFQ 在 FPI 后调节 CSF 强啡肽的释放。这些数据还表明，强啡肽通过 COX-2 激活，在 FPI 后有助于 O-2(-) 的产生。这些数据还表明，强啡肽和 COX-2 激活会导致 FPI 后 NMDA 软脑膜动脉扩张受损。最后，这些数据表明，NOC/oFQ 通过强啡肽的连续释放、COX-2 的激活和 O-2(-) 的产生来损害 NMDA 扩张。
Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O-2(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O-2(-) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH2 attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; -8 +/- 1 and -13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O-2(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O-2(-).