Crotaline (Monocrotaline)
(Synonyms: 野百合碱; Crotaline) 目录号 : GN10512
An alkaloid that induces pulmonary hypertension in rats
Cas No.:315-22-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
HepaRG hepatocytes and HSECs |
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Preparation Method |
HSECs were treated with different concentrations of retrorsine, crotaline (monocrotaline) or clivorine dissolved in ECM containing DMSO (0.5% final concentration) or ECM containing 0.5% DMSO as solvent controls in two-layer transwell co-culture model for 24 h. |
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Reaction Conditions |
100-1200uM,24h |
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Applications |
In the absence of HepaRG hepatocytes, even at significantly high concentration (1200 μM) for 24 h treatment, Crotaline did not affect viability of HSECs, indicating no cytotoxicity. In contrast, after 24 h treatment in the two-layer transwell co-culture model with co-culture of HSECs and HepaRG hepatocytes, significant decrease in HSEC viability in a concentration-dependent manner was observed for Crotaline. |
| Animal experiment [2]: | |
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Animal models |
20 male Sprague Dawley rats (SD; 220-270g) |
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Preparation Method |
Control group received vehicle for crotaline. Pre-pulmonary hypertension (PH) group received a single injection of Crotaline to induce and were sacrificed after 14 days. |
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Dosage form |
A single injection crotaline 60 mg/kg for 14 days |
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Applications |
Changes in multiple pathways associated with PH development were observed by crotaline injection, including activated glycolysis, increased proliferation markers, disruption of carnitine homeostasis, increased inflammatory and fibrotic biomarkers, and decreased glutathione biosynthesis. |
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References: [1]. Lu Y, Ma J, Lin G. Development of a two-layer transwell co-culture model for the in vitro investigation of pyrrolizidine alkaloid-induced hepatic sinusoidal damage. Food Chem Toxicol. 2019 Jul;129:391-398. doi: 10.1016/j.fct.2019.04.057. Epub 2019 May 2. PMID: 31054999. [2]. Nogueira-Ferreira R, Vitorino R, et,al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach. Pulm Pharmacol Ther. 2015 Dec;35:8-16. doi: 10.1016/j.pupt.2015.09.007. Epub 2015 Sep 21. PMID: 26403584. |
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Crotaline is an pyrrolizidine alkaloid extracted from the seeds of the Crotalaria spectabilis plant to induce pulmonary vascular syndrome in rats[1]. crotaline a natural ligand exhibits dose-dependent cytotoxicity with potent antineoplastic activity. The in vitro cytotoxicity of crotaline is proved at IC50 24.966 μg/mL and genotoxicity at 2 X IC50 against HepG2 cells[2].
In the absence of HepaRG hepatocytes, even at significantly high concentration (1200 μM) for 24 h treatment, Crotaline did not affect viability of HSECs, indicating no cytotoxicity. In contrast, after 24 h treatment in the two-layer transwell co-culture model with co-culture of HSECs and HepaRG hepatocytes, significant decrease in HSEC viability in a concentration-dependent manner was observed for Crotaline[8].
Crotaline causes pulmonary vascular syndrome in rats, characterized by proliferative pulmonary vasculitis, pulmonary hypertension (PH), and cor pulmonale[3].Changes in multiple pathways associated with PH development were observed by crotaline injection, including activated glycolysis, increased proliferation markers, disruption of carnitine homeostasis, increased inflammatory and fibrotic biomarkers, and decreased glutathione biosynthesis[5].Using rats (14 days after exposure to crotaline), changes in multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis[4].PAH induced by Crotaline is a progressive disease with persistent inflammation. The inflammation in Crotaline -PAH model includes acute (the first 6 days after Crotaline injection) and chronic stages (after acute inflammation stage). Acute inflammation stage may be the time window of anti-inflammatory treatment in PAH induced by Crotaline [6,7].
References:
[1]: Gomez-Arroyo JG, Farkas L, et,al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 2012 Feb 15;302(4):L363-9. doi: 10.1152/ajplung.00212.2011. Epub 2011 Sep 30. PMID: 21964406.
[2]: Kusuma SS, Tanneeru K, et,al. Antineoplastic activity of monocrotaline against hepatocellular carcinoma. Anticancer Agents Med Chem. 2014;14(9):1237-48. doi: 10.2174/1871520614666140715085907. PMID: 25028149.
[3]: Wilson DW, Segall HJ, et,al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5-6):307-25. doi: 10.3109/10408449209146311. PMID: 1489509.
[4]: Nogueira-Ferreira R, Vitorino R, et,al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach. Pulm Pharmacol Ther. 2015 Dec;35:8-16. doi: 10.1016/j.pupt.2015.09.007. Epub 2015 Sep 21. PMID: 26403584.
[5]: Rafikova O, Meadows ML, et,al. Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. PLoS One. 2016 Mar 3;11(3):e0150480. doi: 10.1371/journal.pone.0150480. PMID: 26937637; PMCID: PMC4777490.
[6]: Tang C, Luo Y, et,al. Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats. Biomed Pharmacother. 2021 Jan;133:111081. doi: 10.1016/j.biopha.2020.111081. Epub 2020 Dec 15. PMID: 33378977.
[7]: Nogueira-Ferreira R, Vitorino R, et,al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach. Pulm Pharmacol Ther. 2015 Dec;35:8-16. doi: 10.1016/j.pupt.2015.09.007. Epub 2015 Sep 21. PMID: 26403584.
[8]: Lu Y, Ma J, Lin G. Development of a two-layer transwell co-culture model for the in vitro investigation of pyrrolizidine alkaloid-induced hepatic sinusoidal damage. Food Chem Toxicol. 2019 Jul;129:391-398. doi: 10.1016/j.fct.2019.04.057. Epub 2019 May 2. PMID: 31054999.
Crotaline 是一种从 Crotalaria spectabilis 植物种子中提取的吡咯里西啶生物碱，可诱导大鼠肺血管综合征[1]。 crotaline 是一种天然配体，具有剂量依赖性细胞毒性和强大的抗肿瘤活性。 crotaline 的体外细胞毒性为 IC50 24.966 μg/mL，对 HepG2 细胞的遗传毒性为 2 X IC50[2]。
在没有 HepaRG 肝细胞的情况下，即使在显着高浓度 (1200 μM) 下处理 24 小时，Crotaline 也不影响 HSEC 的活力，表明没有细胞毒性。相比之下，在 HSECs 和 HepaRG 肝细胞共培养的双层 transwell 共培养模型中处理 24 h 后，观察到 Crotaline 浓度依赖性显着降低 HSEC 活力[8].
Crotaline 引起大鼠肺血管综合征，以增殖性肺血管炎、肺动脉高压 (PH) 和肺心病为特征[3]。通过 crotaline 注射液观察与 PH 发展相关的多条通路的变化，包括激活的糖酵解、增殖标志物增加、肉碱稳态破坏、炎症和纤维化生物标志物增加以及谷胱甘肽生物合成减少[5]。使用大鼠（暴露于 crotaline 后 14 天），多条通路发生变化PH 的发展相关，包括激活的糖酵解、增殖标志物增加、肉碱稳态破坏、炎症和纤维化生物标志物增加以及谷胱甘肽生物合成减少[4]。Crotaline 诱导的 PAH 是一种具有持续炎症的进行性疾病。 Crotaline-PAH模型中的炎症包括急性（Crotaline注射后的前6天）和慢性阶段（急性炎症阶段后）。急性炎症期可能是百合碱诱导PAH抗炎治疗的时间窗[6,7]。
| Cas No. | 315-22-0 | SDF | |
| 别名 | 野百合碱; Crotaline | ||
| 化学名 | (3R,4R,5R,8a1R,13aR)-4,5-dihydroxy-3,4,5-trimethyl-4,5,8,8a1,10,12,13,13a-octahydro-2H-[1,6]dioxacycloundecino[2,3,4-gh]pyrrolizine-2,6(3H)-dione | ||
| Canonical SMILES | O=C([C@@](C([H])([H])[H])([H])[C@@]([C@@]1(C([H])([H])[H])O[H])(C([H])([H])[H])O[H])O[C@@]2([H])[C@](C(C([H])([H])OC1=O)=C([H])C3([H])[H])([H])N3C([H])([H])C2([H])[H] | ||
| 分子式 | C16H23NO6 | 分子量 | 325.15 |
| 溶解度 | ≥ 67.2 mg/mL in DMSO, ≥ 16.45 mg/mL in ETOH with ultrasonic and warming, ≥ 1.66 mg/mL in Water with ultrasonic and warming | 储存条件 | 4°C, away from moisture and light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0755 mL | 15.3775 mL | 30.755 mL |
| 5 mM | 0.6151 mL | 3.0755 mL | 6.151 mL |
| 10 mM | 0.3076 mL | 1.5378 mL | 3.0755 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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2.
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Comparative analysis of age in monocrotaline-induced pulmonary hypertensive rats
J Pharmacol Sci2021 Sep;147(1):81-85.PMID: 34294376DOI: 10.1016/j.jphs.2021.05.012
Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal cardiovascular/lung disease. The incidence rate is affected by age. Monocrotaline (MCT, 60 mg/kg)-treated rats are widely used as an experimental PAH model. Here, we found that young rats died at a mean of 23.4 days after MCT injection, whereas adult rats survived for over 42 days. However, young (7-week-old) and adult (20-week-old) MCT-treated rats developed PAH, and had upregulated Ca2+-sensing receptor and transient receptor potential canonical subfamily 6 channel expression in pulmonary arteries. The present study provides novel information for elucidating the mechanism underlying the age difference in PAH patients.
[Pulmonary artery denervation in pulmonary hypertension: physiological and clinical aspects]
Angiol Sosud Khir2021;27(3):16-21.PMID: 34528584DOI: 10.33529/ANGIO2021309
This article is a review of the findings of experimental and clinical studies of a new method of treatment of pulmonary hypertension - pulmonary artery denervation with the help of radiofrequency ablation, cryodenervation and ultrasonic impact. Pulmonary artery denervation results in decreased neurogenic tonic sympathetic and, probably, increased parasympathetic effects on pulmonary vessels. On models of experimental monocrotaline-induced pulmonary hypertension in various-species animals, it was determined that pulmonary artery denervation is followed by decreased activity of local pulmonary renin-angiotensin system, slowed processes of remodeling of pulmonary vessels, hypertrophy and fibrosis of the right ventricle, with inhibition of progression of pulmonary hypertension by means of suppression of extracellular signal-regulated kinase 1/2 (ERK 1/2) which regulates differentiation, proliferation and migration of smooth muscle cells. However, the problem of the pattern of pulmonary microcirculation changes (pre- and postcapillary resistance, capillary filtration coefficient) after pulmonary artery denervation warrants further study. The findings of clinical studies in patients with pulmonary hypertension suggest that pulmonary artery denervation inducing a decrease of pressure therein, as well as pulmonary vessel resistance did not lead to normalization of pulmonary haemodynamics.The mentioned impact partially removes the neurogenic component of multicircuit and multifactorial regulation of pulmonary circulation. Therefore, along with pulmonary artery denervation, further search for pharmacological agents selectively influencing pulmonary vessels remains a problem of current importance.
Mesenchymal Stromal Cell-derived Exosomes Attenuate Experimental Pulmonary Arterial Hypertension
Curr Pharm Biotechnol2021;22(12):1654-1662.PMID: 33390109DOI: 10.2174/1389201022666201231113127
Background: Pulmonary arterial Hypertension (PH) is a chronic disease that ultimately progresses to right ventricular failure and death. Until now, there is still a lack of effective treatment applied. The purpose of the present study was to observe the protective effect of Mesenchymal Stromal Cell-Derived Exosomes (MSC-EXO) against experimental Pulmonary arterial Hypertension (PH) and right ventricular failure.
Methods: All the experimental rats received an intraperitoneal injection of 50 mg/kg monocrotaline to induce PH model. Three weeks after the model was successfully established, the cell Culture Media (CM) or MSC-EXO derived from human umbilical cord was administered daily via the tail vein. All animals were randomly divided into 4 groups: Control (saline-treated), MCT-PH, MCT-CM and MCT-EXO groups. Post-operation, hemodynamic data and index of right ventricular hypertrophy (RVHI) were recorded to evaluate the inhibition of MSC-EXO on MCT-induced PH. Histology, immunohistochemistry and western blot were used to analyze the effect of MSC-EXO against vascular remodeling and further reveal the mechanism.
Results: In the present study, our results showed that MSC-EXO administration could significantly reduce the Right Ventricular Systolic Pressure (RVSP) and RVHI, suppress the pulmonary vascular remodeling and The Endothelial-Mesenchymal Transition (EndMT) process.
Conclusion: Our results provided the firm information for a new method in the treatment of PH; the mechanism may be related to the inhibition of vascular remodeling and EndMT.
Recovery of Liver Sinusoidal Endothelial Cells Following Monocrotaline-induced Liver Injury
In Vivo2021 Sep-Oct;35(5):2577-2587.PMID: 34410945DOI: 10.21873/invivo.12540
Background/aim: Although the pathology of sinusoidal obstruction syndrome (SOS) is characterized by damage to liver sinusoidal endothelial cells (LSECs), the processes underlying LSEC repair are incompletely understood. The angiopoietin (Ang)/Tie system contributes to angiogenesis. The present study aimed to examine the processes of LSEC repair and the involvement of the Ang/Tie pathway in LSEC recovery.
Materials and methods: Experimentally, SOS was induced by intraperitoneal injection of monocrotaline (MCT) to C57/BL6 mice.
Results: Levels of LSEC markers were up-regulated during the repair phase of MCT-induced hepatotoxicity. The damaged LSECs recovered from the injury by expanding LSECs expressing lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in the peri-central area of MCT-injured livers, while LSECs in the same area of uninjured livers lacked LYVE-1 expression. Bone marrow (BM)-derived cells did not incorporate into the restored LSECs. Tie2 expression was related to LSEC recovery in MCT-injured liver tissue.
Conclusion: The resident LSECs neighboring uninjured tissue replace damaged LSECs in MCT-injured livers. Tie2 is involved in LSEC recovery from MCT-induced hepatotoxicity.
Influence of atorvastatin on metabolic pattern of rats with pulmonary hypertension
Aging (Albany NY)2021 Apr 22;13(8):11954-11968.PMID: 33886502DOI: 10.18632/aging.202898
Background: Metabonomics has been widely used to analyze the initiation, progress, and development of diseases. However, application of metabonomics to explore the mechanism of pulmonary arterial hypertension (PAH) are poorly reported. This study aimed to investigate the influence of atorvastatin (Ato) on metabolic pattern of rats with pulmonary hypertension.
Methods: PAH animal model was established using monocrotaline (MCT). The mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were measured. The microstructure of pulmonary arterioles was observed by HE staining. Nuclear magnetic resonance was used to detect and analyze the serum metabolites. The levels of glycogen synthase kinase-3β (GSK-3β), hexokinase 2 (HK-2), sterol regulatory element-binding protein 1c (SREBP-1c), and carnitine palmitoyltransferase I (CPT-1) in the lung tissues were measured.
Results: Ato significantly improved lung function by decreasing mPAP, RVHI, wall thickness, and wall area. Differences in metabolic patterns were observed among normal, PAH, and Ato group. The levels of GSK-3β and SREBP-1c were decreased, but HK-2 and CPT-1 were increased in the group PAH. Ato treatment markedly reversed the influence of MCT.
Conclusion: Ato significantly improved the pulmonary vascular remodeling and pulmonary hypertension of PAH rats due to its inhibition on Warburg effect and fatty acid β oxidation.