Bursa Provincial Health Directorate, T.C. Ministry of Health, Bursa, Turkey.
Department of Medical Pharmacology, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey.
Neurol Res. 2022 Oct;44(10):927-936. doi: 10.1080/01616412.2022.2072100. Epub 2022 May 2.
We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and determine the possible mechanisms.
Extracellular concentrations of dopamine were measured using acute brain slices method under hypoxic, aglycemic and ischemic conditions. Sigma receptor ligands haloperidol and ifenprodil attenuate striatal dopamine release induced by hypoxia in contrast to aglycemia and ischemia. To determine the possible contribution of glutamatergic system on this effect, we compared the effect of NMDA receptor antagonist MK-801 and haloperidol in hypoxia induced by Na-K-ATPaz enzyme inhibitor ouabain. Also, we compared the effect of dopamine uptake blocker nomifensine and haloperidol to determine the role of dopamine transporter on this effect.
Haloperidol and nomifensine almost completely abolish ouabain-induced dopamine release unlike MK-801. Different effects of sigma ligands and glutamate receptor antagonists on the hypoxia and ouabain induced dopamine release show that glutamate receptor blockade is partial involved in inhibitory effect of sigma ligand on dopamine release under hypoxic conditions. Similar effect of dopamine uptake blocker nomifensine and sigma receptor ligand haloperidol on ouabain induced dopamine release supports the possibility that inhibition of reverse dopamine transport by sigma ligands might be involved in their protective effect.
Data in this study suggest that sigma ligands may be a new therapeutic intervention for the management of hypoxic conditions.
我们旨在验证这样一个假说，即 sigma 受体配体氟哌啶醇和ifenprodil 可减弱体外缺氧诱导的纹状体多巴胺释放，并确定其可能的机制。
在缺氧、低糖和缺血条件下，采用急性脑切片法测量细胞外多巴胺浓度。与低糖和缺血相比，sigma 受体配体氟哌啶醇和ifenprodil 可减弱缺氧诱导的纹状体多巴胺释放。为了确定谷氨酸能系统对此作用的可能贡献，我们比较了 NMDA 受体拮抗剂 MK-801 和氟哌啶醇在 Na-K-ATPaz 酶抑制剂哇巴因诱导的缺氧中的作用。此外，我们比较了多巴胺摄取阻滞剂 nomifensine 和氟哌啶醇的作用，以确定多巴胺转运体在此作用中的作用。
氟哌啶醇和 nomifensine 几乎完全消除了哇巴因诱导的多巴胺释放，而 MK-801 则没有。sigma 配体和谷氨酸受体拮抗剂对缺氧和哇巴因诱导的多巴胺释放的不同作用表明，谷氨酸受体阻断部分参与了 sigma 配体在缺氧条件下对多巴胺释放的抑制作用。多巴胺摄取阻滞剂 nomifensine 和 sigma 受体配体氟哌啶醇对哇巴因诱导的多巴胺释放的相似作用支持这样一种可能性，即 sigma 配体抑制反向多巴胺转运可能与其保护作用有关。
本研究数据表明，sigma 配体可能是治疗缺氧条件的一种新的治疗干预手段。
