Wallace David R, Dodson Summer L, Nath Avindra, Booze Rosemarie M
Oklahoma State University, Center for Health Sciences, Departments of Pharmacology, Physiology and Forensic Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898, USA.
Neurotoxicology. 2006 Jan;27(1):101-7. doi: 10.1016/j.neuro.2005.07.008. Epub 2005 Sep 15.
Previous reports have indicated that the use of delta agonists may prove to be a viable therapeutic tool as an analgesic agent without conventional opioid side effects. In addition, recent evidence suggests that delta ligands may exert neuroprotective effects under a variety of toxin insults. The aim of the present studies was to assess the ability of delta agonists (peptide: [D-Pen(2,5)] enkephalin (DPDPE), non-peptide: (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80)) and antagonists (naltrindole) to modify dichlorofluorescein (DCFH) fluorescence in the presence of the peroxynitrite generator, 3-morpholinylsydnoneimine chloride (SIN-1) or HIV-protein, TAT(1-72) (TAT) in SK-N-SH cells. Both DPDPE (100 nM) and SNC-80 (250 nM) attenuated (30-50%) the increased oxidative stress in the presence of SIN-1. This effect was partially reversed by addition of naltrindole, suggesting involvement of delta receptors. Peroxynitrite radicals are involved in neurotoxicity associated with TAT. Incubation with TAT (10-250 nM) demonstrated a concentration-dependent increase in oxidative stress up to 200% over control values. Preincubation with delta agonists reduced 50 nM TAT-mediated oxidative stress 15-40%, which was partially reversed by naltrindole. Increasing log-concentrations of DPDPE or SNC-80 (0.01-100 microM) attenuated TAT-mediated oxidative stress up to 50% at 100 microM. In conclusion, these data demonstrate that both peptide and non-peptide delta agonists can partially attenuate intracellular oxidative stress, in part through a receptor-mediated mechanism. This suggests that delta ligands may have therapeutic usefulness in HIV patients beyond analgesia.
先前的报告表明，使用δ激动剂可能被证明是一种可行的治疗工具，作为一种镇痛剂且无传统阿片类药物的副作用。此外，最近的证据表明，δ配体在多种毒素损伤下可能发挥神经保护作用。本研究的目的是评估δ激动剂（肽类：[D-青霉胺(2,5)]脑啡肽(DPDPE)，非肽类：(+)-4-[(aR)-a-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基]-N,N-二乙苯甲酰胺(SNC-80)）和拮抗剂（纳曲吲哚）在过氧亚硝酸盐生成剂3-吗啉代辛二酮盐酸盐(SIN-1)或HIV蛋白TAT(1-72)(TAT)存在的情况下对SK-N-SH细胞中2,7-二氯荧光素(DCFH)荧光的影响。在SIN-1存在的情况下，DPDPE(100 nM)和SNC-80(250 nM)均能减轻(30 - 50%)氧化应激的增加。加入纳曲吲哚后，这种作用部分被逆转，提示δ受体参与其中。过氧亚硝酸盐自由基参与了与TAT相关的神经毒性。与TAT(10 - 250 nM)孵育显示氧化应激呈浓度依赖性增加，比对照值高出200%。用δ激动剂预孵育可使50 nM TAT介导的氧化应激降低15 - 40%，纳曲吲哚可部分逆转这种作用。增加DPDPE或SNC-80的对数浓度(0.01 - 100 microM)可使TAT介导的氧化应激在100 microM时降低达50%。总之，这些数据表明，肽类和非肽类δ激动剂均可部分减轻细胞内氧化应激，部分是通过受体介导的机制。这表明δ配体在HIV患者中可能具有除镇痛之外的治疗作用。
