Rehabilitation Research Center, Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran.
Department of Neurosciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Neurotox Res. 2020 Jun;38(1):38-49. doi: 10.1007/s12640-020-00183-3. Epub 2020 Feb 27.
Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3', 5'-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 μg/side), bucladesine (10 and 100 μM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.
全身给予 3,4-亚甲二氧基甲基苯丙胺（MDMA）的神经毒性作用归因于 MDMA 及其代谢物。然而，母体化合物在 MDMA 诱导的线粒体和记忆损伤中的作用尚未得到研究。此外，尚未研究 3',5'-环腺苷酸单磷酸（cAMP）的类似物是否可以降低 MDMA 的这些神经毒性作用。我们希望研究 MDMA 对空间记忆和线粒体功能的中枢给药作用，以及 cAMP 的膜可渗透类似物布克拉德西（bucladesine）对 MDMA 这些作用的影响。我们评估了双侧海马内预先训练输注 MDMA（0.01、0.1、0.5 和 1μg/侧）、布克拉德西（10 和 100μM）或它们的组合对空间记忆以及海马线粒体功能的不同参数的影响，包括活性氧（ROS）产生水平、线粒体膜电位（MMP）、线粒体肿胀、线粒体外膜损伤、细胞色素 c 释放量以及海马 ADP/ATP 比。结果表明，MDMA 导致空间记忆损伤和线粒体功能障碍，这表现为海马 ADP/ATP 比、ROS 水平、MMP 崩溃、线粒体肿胀和线粒体外膜损伤显著增加，导致细胞色素 c 从线粒体释放。本研究还发现布克拉德西显著降低了 MDMA 的破坏性作用。这些结果提供了证据表明，母体化合物（MDMA）通过线粒体功能障碍在 MDMA 诱导的记忆损伤中起作用。本研究强调了 cAMP/PKA 信号在 MDMA 诱导的记忆和线粒体缺陷中的作用。
