Morota Saori, Månsson Roland, Hansson Magnus J, Kasuya Kazuhiko, Shimazu Motohide, Hasegawa Erika, Yanagi Shigeru, Omi Akibumi, Uchino Hiroyuki, Elmér Eskil
Department of Clinical Sciences, Lund University, Sweden.
Exp Neurol. 2009 Aug;218(2):353-62. doi: 10.1016/j.expneurol.2009.03.036. Epub 2009 Apr 5.
Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation, can also occur independently of the mPT phenomenon. Here, in isolated rodent brain-derived and human liver mitochondria, we re-evaluate drugs promoted as potent mPT inhibitors. We address the definition of an mPT inhibitor and present strategies to reliably detect mPT inhibition in vitro. Surprisingly, none of the 12 compounds tested displayed convincing mPT inhibition or effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla(3)-EtVal(4)-Cyclosporin (Debio 025). Propofol and 2-aminoethoxydiphenyl borate (2-APB) inhibited swelling in de-energized mitochondria but did not increase calcium retention capacity (CRC). Progesterone, trifluoperazine, allopregnanolone and 4-hydroxy-tamoxifen dose-dependently reduced CRC and respiratory control and were thus toxic rather than beneficial to mitochondrial function. Interestingly, topiramate increased CRC at high concentrations likely by a mechanism separate from direct mPT inhibition. We conclude that a clinically relevant mPT inhibitor should have a mitochondrial target and increase mitochondrial calcium retention at concentrations which can be translated to human use.
抑制线粒体通透性转换（mPT）已成为一种有前景的神经保护方法，因此迫切需要开发具有良好血脑屏障穿透性且耐受性良好的mPT抑制剂。在最近的一项研究中，28种具有常见杂环结构的临床可用药物被鉴定为mPT抑制剂，例如三氟拉嗪、异丙嗪和去甲替林。此外，结构不相关的药物如神经甾体、4-羟基他莫昔芬和曲美他嗪的神经保护作用也归因于对mPT的直接抑制。mPT的调节很复杂，并且高度依赖于当前的实验条件。mPT的一些特征，如肿胀、去极化或NADH氧化，也可能独立于mPT现象而发生。在此，我们在分离的啮齿动物脑源线粒体和人肝线粒体中，重新评估被认为是强效mPT抑制剂的药物。我们探讨了mPT抑制剂的定义，并提出了在体外可靠检测mPT抑制的策略。令人惊讶的是，所测试的12种化合物中没有一种表现出令人信服的mPT抑制作用或与非免疫抑制性亲环素抑制剂D-MeAla(3)-EtVal(4)-环孢素（Debio 025）抑制亲环素D的效果相当。丙泊酚和2-氨基乙氧基二苯硼酸盐（2-APB）抑制了去能线粒体中的肿胀，但没有增加钙保留能力（CRC）。孕酮、三氟拉嗪、别孕烯醇酮和4-羟基他莫昔芬剂量依赖性地降低了CRC和呼吸控制，因此对线粒体功能有毒而非有益。有趣的是，托吡酯在高浓度下可能通过与直接mPT抑制不同的机制增加了CRC。我们得出结论，一种临床相关的mPT抑制剂应该具有线粒体靶点，并在可转化为人体使用的浓度下增加线粒体钙保留。
