PDE4

(+)-Rolipram（0.015-1000 μM；20 小时）以剂量依赖性方式抑制 LPS 产生的人单核细胞 (MNC) TNF 的 IC50 为 550 nM[1]。

(+)-咯利普兰剂量依赖性地抑制大鼠的运动活动并引起头部抽搐（0.025–6.25 mg/kg；腹膜内注射）[2]。当腹腔注射 0.06–25 mg/kg (+)-咯利普兰时，大鼠的直肠温度随剂量成比例下降[2]。

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在食物驱动的双杠杆操作任务中，训练Long Evans大鼠区分0.2mg/kg IP（+/-）-rolipram和赋形剂注射。九只大鼠中有八只在平均91次训练后获得了辨别力（最小65次，最大137次）。（+/-）-罗利普兰的ED50为0.06mg/kg IP。对（-）-和（+）-罗利普兰的泛化测试表明，（-）异构体的活性是（+）罗利普兰的8倍，ED50分别为0.06和0.4 mg/kg IP。磷酸二酯酶抑制剂RO 20-1724在0.6和1.0 mg/kg IP的剂量下部分（83%）推广到（+/-）-罗利普兰。IBMX 5mg/kg IP显示63%的泛化率。对丙咪嗪和去甲肾上腺素摄取抑制剂奥沙普林的（+）-和（-）-异构体的测试表明，NA摄取抑制药物不会形成（+/-）-罗利普兰样的感受内线索。dbcAMP 12.5mg/kg SC和100mg/kg SC dbcGMP不能推广到训练药物。这种剂量的（+/-）-罗利普兰在大鼠体内产生的鉴别刺激的性质仍有待阐明[3]。

用罗利普兰抑制PDE4以表皮生长因子受体依赖的方式促进P2Y11/IL-1R诱导的CXCR7表达和CCL20产生的上调。使用天然表达CXCR7但缺乏CXCR4的星形细胞瘤细胞系，P2Y11/IL-1R激活有效地诱导了CCL20的产生，即使在没有PDE4抑制的情况下，CXCR7激动剂TC14012也能增强CCL20的生产。此外，RNA干扰导致的CXCR7耗竭抑制了CCL20的产生。在巨噬细胞中，P2Y11和CXCR7被其各自的激动剂同时激活足以诱导CCL20的产生，而不需要PDE4的抑制，因为CXCR7的激活增加了其自身并消除了CXCR4的表达。最后，对巨噬细胞分泌组中多种CCL趋化因子的分析表明，CXCR4失活和CXCR7活化选择性地增强了P2Y11/IL-1R介导的CCL20分泌。总之，我们的数据确定CXCR7是P2Y11/IL-1R启动的信号级联的组成部分，CXCR4相关的PDE4是调节检查点。Cell Mol Life Sci. 2024 Mar 13;81(1):132.

抑制肿瘤坏死因子α产生的化合物在感染性休克动物模型中具有保护作用。最近的研究表明，黄嘌呤衍生物具有有益的作用，它通过充当非特异性cAMP磷酸二酯酶抑制剂来抑制肿瘤坏死因子α的产生。在这个实验中，我们测试了（+/-）-罗利普兰（外消旋体）及其对映体对脂多糖（LPS）刺激的人单核细胞的影响。罗利普兰具有苯基吡咯烷酮结构，与甲基黄嘌呤无关，是IV型磷酸二酯酶的特异性抑制剂。我们的研究结果表明，罗利普兰是LPS诱导的肿瘤坏死因子α合成的一种非常有效的抑制剂。与非特异性抑制剂己酮可可碱相比，（+/-）-罗利普兰（130 nM）的IC50低500多倍。罗利普兰对肿瘤坏死因子α产生的影响取决于分子的空间构型，因为（-）-对映体的IC50比（+）-对异构体低五倍。所有受试物质的抑制作用对肿瘤坏死因子α而非白细胞介素-1β具有选择性，因为白细胞介蛋白-1β的产生仅受到轻微影响[1]。

This study aimed to investigate the effects of rolipram, a phosphodiesterase inhibitor, on brain tissue regeneration. Trimethyltin-injected mice, an animal model of hippocampal tissue regeneration, was created by a single injection of trimethyltin chloride (2.2 mg/kg, intraperitoneally). Daily rolipram administration (10 mg/kg, intraperitoneally) was performed from the day after trimethyltin injection until the day before sampling. In Experiment 1, brain samples were collected on day 7 postinjection of trimethyltin following the forced swim test. In Experiment 2, bromodeoxyuridine (150 mg/kg, intraperitoneally/day) was administered on days 3-5 and sampling was on day 21 postinjection of trimethyltin. Samples were routinely embedded in paraffin and sections were obtained for histopathological investigation. In Experiment 1, rolipram-treated mice showed shortened immobility times in the forced swim test. Histopathology revealed that rolipram treatment had improved the replenishment of neuronal nuclei-positive neurons in the dentate gyrus, which was accompanied by an increase in the percentage of phosphorylated cyclic AMP response element-binding protein-positive cells. In addition, rolipram had decreased the percentage of ionized calcium-binding adapter protein 1-positive microglia with activated morphology and the number of tumor necrosis factor-alpha-expressing cells. In Experiment 2, double immunofluorescence for bromodeoxyuridine/neuronal nuclei revealed an increase of double-positive cells in rolipram-treated mice. These results demonstrate that rolipram effectively promotes brain tissue regeneration by enhancing the survival of newborn neurons and inhibiting neuroinflammation.Neuroreport. 2024 Sep 4;35(13):832-838.

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Dissolved in 100% PEG at an appropriate concentration; 1 mL/kg; i.v. injection

Male Hartley guinea pigs

[1]. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol. 1993 Apr;15(3):409-13.

[2]. Wachtel H. Neurotropic effects of the optical isomers of the selective adenosine cyclic 3',5'-monophosphate phosphodiesterase inhibitor rolipram in rats in-vivo. J Pharm Pharmacol. 1983 Jul;35(7):440-4.

[3]. Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats. Psychopharmacology (Berl). 1986;89(3):273-7.

Compounds suppressing the production of tumor necrosis factor-alpha are protective in animal models of septic shock. Recent studies demonstrated a beneficial effect of xanthine derivatives, which suppress tumor necrosis factor-alpha production by acting as non-specific cAMP phosphodiesterase inhibitors. In this experiment we tested the effect of (+/-)-rolipram (racemate) and its enantiomers on human mononuclear cells stimulated with lipopolysaccharide (LPS). Rolipram has a phenyl-pyrrolidinone structure, unrelated to the methylxanthines, and acts as a specific inhibitor of the type IV phosphodiesterase. Our results identify rolipram as a remarkably potent suppressor of the LPS-induced synthesis of tumor necrosis factor-alpha. When compared to the non-specific inhibitor pentoxifylline, the IC50 of (+/-)-rolipram (130 nM) is more than 500 times lower. The influence of rolipram on tumor necrosis factor-alpha production depended on the steric configuration of the molecule, since the (-)-enantiomer exhibited a five times lower IC50 than the (+)-enantiomer. The inhibitory effect of all substances tested is selective for tumor necrosis factor-alpha rather than interleukin-1 beta, since interleukin-1 beta production is only slightly influenced. [1]

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The efficacy of the selective adenosine cyclic 3',5'-monophosphate (cAMP) phosphodiesterase (PDE) inhibitor (+/-)-rolipram and its optical isomers (0.006 to 25 mg kg-1) in inducing characteristic behavioural changes like hypothermia, hypoactivity, forepaw shaking, grooming and head twitches in rats has been examined. (+)-Rolipram was found some 15 times less potent than the racemate suggesting a stereoselective interaction with a rat brain cAMP phosphodiesterase isoenzyme. Following their intracerebral administration, the stereoisomers also demonstrated their unusual potency ratio. These findings suggested that (+)-rolipram is a less potent neurotropic PDE inhibitor in-vivo than its (-)-enantiomer.[2]

C16H21NO3

275.34

275.152

C, 69.79; H, 7.69; N, 5.09; O, 17.43

85416-73-5

Rolipram;61413-54-5;(R)-(-)-Rolipram;85416-75-7

158758

Off-white to light yellow solid powder

1.2±0.1 g/cm3

472.7±45.0 °C at 760 mmHg

133-136ºC

239.7±28.7 °C

0.0±1.2 mmHg at 25°C

1.552

1.43

47.56

COC1=C(C=C(C=C1)[C@@H]2CC(=O)NC2)OC3CCCC3

HJORMJIFDVBMOB-GFCCVEGCSA-N

InChI=1S/C16H21NO3/c1-19-14-7-6-11(12-9-16(18)17-10-12)8-15(14)20-13-4-2-3-5-13/h6-8,12-13H,2-5,9-10H2,1H3,(H,17,18)/t12-/m1/s1

(4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.08 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 (9.08 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 (9.08 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 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% propylene glycol:10 mg/L

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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。