Olesoxime (TRO-19622)   中文名称: 奥利索西

Mitochondrial; neuroprotective

在不使用来自大脑、睫状体或胶质细胞的神经营养因子的情况下，原代胚胎大鼠脊髓 MN 在接种一小时后暴露于浓度范围为 0.1 至 10 µM 的 Olesoxime (TRO 19622) 中，可显着防止细胞损伤和死亡。这种保护在培养物中持续了三天。浓度为 10 µM 的 Olesoxime (TRO 19622) 通过神经营养因子混合物（包括大脑、睫状体和神经胶质细胞产生的因子）的作用维持 74±10% 的神经元存活。在此测试中，平均 EC50 为 3.2±0.2 µM。 Olesoxime (TRO 19622) 不仅可以保护 MN 细胞体，还可以促进神经突发育。在 1 µM 浓度下，olesoxime (TRO 19622) 仅略微提高细胞活力，但显着促进每个细胞的神经突发育达 54% [1]。人们发现了一类新型胆固醇肟，称为 olesoxime (TRO 19622)，因为它能够在缺乏神经营养因子的情况下提高纯运动神经元的存活率。 Olesoxime (TRO 19622) 选择性地靶向线粒体外膜中的蛋白质，重点关注线粒体并抑制氧化应激介导的通透性转变孔开放等过程[2]。

成年小鼠每天皮下注射 Olesoxime (TRO 19622)（3 或 30 mg/kg）超过两个月，耐受性良好，没有毒性或不良反应 [1]。当动物在损伤后口服治疗五天时，Olesoxime (TRO 19622) 以剂量依赖性方式增加运动神经元细胞体的存活率；在此剂量下，运动神经元存活率为 29 ±2% (n=18)，与载体治疗的动物相比，存活率增加了 42% [3]。接受 3 mg/kg/d 或 30 mg/kg/d Olesoxime (TRO 19622) 预防性治疗的紫杉醇治疗大鼠分别具有 239±17.6 和 247±14.4 IENF/cm。对于两种剂量，下降幅度均显着小于用媒介物施用紫杉醇治疗的大鼠中观察到的 46%。

肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是皮层和脊髓运动神经元的逐渐死亡，目前尚无有效的治疗方法。使用能够在体外预防运动神经元细胞死亡的化合物的基于细胞的测定法，筛选了大约40000种低分子量化合物，以确定潜在的小分子治疗方法。我们报道了胆甾-4-烯-3-酮肟（TRO19622）作为治疗ALS的潜在候选药物的鉴定。在体外，TRO19622在缺乏营养支持的情况下以剂量依赖的方式促进运动神经元的存活[3]。

In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1G93A transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases[3].

[1]. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010 Aug;13(8):568-80.

[2]. Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound. Pharmaceuticals (Basel). 2010 Jan 28;3(2):345-368.

[3]. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007 Aug;322(2):709-20.

[4]. Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel. Pain. 2009 Dec 15;147(1-3):202-9.

Olesoxime is a cholesterol-like small molecule that has demonstrated a remarkable neuroprotective profile in a battery of both in vitro and in vivo preclinical models. For example, it has demonstrated the ability to prevent neurodegeneration, enhance nerve function and accelerate neuroregeneration following nerve trauma.

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Drug Indication
Investigated for use/treatment in neurologic disorders.
Treatment of spinal muscular atrophy

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Mechanism of Action
Olesoxime interacts with a physiologically relevant target: the mitochondrial permeability transition pore (mPTP). Mitochondria are central mediators of cell death and are implicated in most if not all neurodegenerative diseases regardless of the initiating factor: genetic mutations, excitotoxicity, reactive oxygen species, ischemia, chemical toxicity, etc. Mitochondria play diverse roles in all cells. In neurons, especially near synaptic sites, mitochondria are essential calcium-buffering organelles in areas where membrane excitability leads to large influx of calcium through calcium channels. Mitochondria also produce the ATP necessary for microtubule-based axoplasmic transport and maintaining the activity of ion and nutrient transporters. If a neuron fails to establish or maintain its functional role, mitochondria are responsible for eliminating it by releasing apoptotic factors. Olesoxime, by interacting with protein components of the mPTP, prevents the release of these apoptotic factors and therefore protects the neuron. This mechanism of action may lead to a general neuroprotective activity with utility in other therapeutic indications.

C27H45NO

399.6523

399.35

C, 81.14; H, 11.35; N, 3.50; O, 4.00

22033-87-0

76971721

Typically exists as white to off-white solids at room temperature

1.1

510ºC at 760mmHg

145-148ºC

341ºC

1.56E-12mmHg at 25°C

1.583

7.858

32.59

1

2

5

29

663

7

C[C@@]12C(CC[C@]3([H])[C@]2([H])CC[C@@]4(C)[C@@]3([H])CC[C@@]4([C@]([H])(C)CCCC(C)C)[H])=CC(CC1)=NO

QNTASHOAVRSLMD-SIWSWZRQSA-N

InChI=1S/C27H45NO/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28-29)13-15-26(20,4)25(22)14-16-27(23,24)5/h17-19,22-25,29H,6-16H2,1-5H3/b28-21+/t19-,22+,23-,24+,25+,26+,27-/m1/s1

(8S,9S,10R,13R,14S,17R,E/Z)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one oxime

E/Z-olesoxime; NSC 21311; NSC-21311; NSC21311; TRO-19622; TRO19622; TRO19622; RG6083; RG 6083; RG-6083;Olesoxime; Olesoxime, Z-; 22033-87-0; UNII-I2QN18P645; I2QN18P645; 66514-00-9; TRO 19622; (NE/Z)-N-[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-ylidene]hydroxylamine;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~125.11 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.26 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.26 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.26 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。