LM11A-31
目录号 : GC25581LM11A-31 is a small molecule p75NTR Ligand that reverses cholinergic neurite dystrophy in alzheimer's diseasemousemodels with mid- to late-stage disease progression
Cas No.:289475-77-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >96.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LM11A-31 is a small molecule p75NTR Ligand that reverses cholinergic neurite dystrophy in alzheimer's diseasemousemodels with mid- to late-stage disease progression.
LM11A-31 greatly reduces or eliminates the neuronal pathology as well as the FIV effects on astrocytes and microglia in an infectious in vitro model, indicating an excellent potential for the treatment of HIV-associated neurodegeneration.[1]
LM11A-31 is a small molecular p75NTR ligand, which reverses cholinergic neurite dystrophy in mice with advanced Alzheimer's disease.[2]
[1] Meeker RB, et al. J Neuroimmune Pharmacol. 2012 Jun;7(2):388-400. "[2] Danielle A Simmons, et al. PLoS One . 2014 Aug 25;9(8):e102136.
| Cas No. | 289475-77-0 | SDF | Download SDF |
| 分子式 | C12H25N3O2 | 分子量 | 243.35 |
| 溶解度 | DMSO: 49 mg/mL (201.36 mM);Water: 49 mg/mL (201.36 mM);Ethanol: 49 mg/mL (201.36 mM) | 储存条件 | Store at -20°C |
| 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。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 4.1093 mL | 20.5465 mL | 41.0931 mL |
| 5 mM | 0.8219 mL | 4.1093 mL | 8.2186 mL |
| 10 mM | 0.4109 mL | 2.0547 mL | 4.1093 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery
J Pharmacol Exp Ther 2022 Feb;380(2):126-141.PMID:34893553DOI:10.1124/jpet.121.000711.
The aim of this study was to test whether poststroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle-treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke-induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks after stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31-treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31-treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75NTR for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENT: The findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer's disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.
Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury
J Sex Med 2021 Jan;18(1):17-28.PMID:33243690DOI:10.1016/j.jsxm.2020.10.015.
Background: Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI), but also causes cavernous hypoxia and cavernous structural changes, which lead to a poor response to phosphodiesterase 5 inhibitors. Aim: To investigate the therapeutic effect of oral administration of LM11A-31, a small molecule p75 neurotrophin receptor (p75NTR) ligand and proNGF antagonist, in a mouse model of bilateral CNI, which mimics nerve injury-induced erectile dysfunction after radical prostatectomy. Methods: 8-week-old male C57BL/6 mice were divided into sham operation and CNI groups. Each group was divided into 2 subgroups: phosphate-buffered saline and LM11A-31 (50 mg/kg/day) being administered once daily starting 3 days before CNI via oral gavage. 2 weeks after CNI, we measured erectile function by electrical stimulation of the bilateral cavernous nerve. The penis was harvested for histologic examination and Western blot analysis. The major pelvic ganglia was harvested and cultured for assays of ex vivo neurite outgrowth. Outcomes: Intracavernous pressure, neurovascular regeneration in the penis, in vivo or ex vivo functional evaluation, and cell survival signaling were measured. Results: Erectile function was decreased in the CNI group (44% of the sham operation group), while administration of LM11A-31 led to a significant improvement of erectile function (70% of the sham operation group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal processes. Immunohistochemical and Western blot analyses showed significantly increased p75NTR expression in the dorsal nerve of CNI mice, which was attenuated by LM11A-31 treatment. Protein expression of active PI3K, AKT, and endothelial nitric oxide synthase was increased, and cell death and c-Jun N-terminal kinase signaling was significantly attenuated after LM11A-31 treatment. Furthermore, LM11A-31 promoted neurite sprouting in cultured major pelvic ganglia after lipopolysaccharide exposure. Clinical implications: LM11A-31 may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases. Strengths & limitations: Unlike biological therapeutics, such as proteins, gene therapies, or stem cells, the clinical application of LM11A-31 would likely be relatively less complex and low cost. Our study has some limitations. Future studies will assess the optimal dosing and duration of the compound. Given its plasma half-life of approximately 1 hour, it is possible that dosing more than once per day will provide added efficacy. Conclusion: Specific inhibition of the proNGF-p75NTR degenerative signaling via oral administration of LM11A-31 represents a novel therapeutic strategy for erectile dysfunction induced by nerve injury. Yin GN, Ock J, Limanjaya A, et al. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2021;18:17-28.
Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway
Diabetologia 2019 Aug;62(8):1488-1500.PMID:31073629DOI:10.1007/s00125-019-4885-2.
Aims/hypothesis: Breakdown of the inner blood-retinal barrier (BRB) is an early event in the pathogenesis of diabetic macular oedema, that eventually leads to vision loss. We have previously shown that diabetes causes an imbalance of nerve growth factor (NGF) isoforms resulting in accumulation of its precursor proNGF and upregulation of the p75 neurotrophin receptor (p75NTR), with consequent increases in the activation of Ras homologue gene family, member A (RhoA). We also showed that genetic deletion of p75NTR in diabetes preserved the BRB and prevented inflammatory mediators in retinas. This study aims to examine the therapeutic potential of LM11A-31, a small-molecule p75NTR modulator and proNGF antagonist, in preventing diabetes-induced BRB breakdown. The study also examined the role of p75NTR/RhoA downstream signalling in mediating cell permeability. Methods: Male C57BL/6 J mice were rendered diabetic using streptozotocin injection. After 2 weeks of diabetes, mice received oral gavage of LM11A-31 (50 mg kg-1 day-1) or saline (NaCl 154 mmol/l) for an additional 4 weeks. BRB breakdown was assessed by extravasation of BSA-AlexaFluor-488. Direct effects of proNGF were examined in human retinal endothelial (HRE) cells in the presence or absence of LM11A-31 or the Rho kinase inhibitor Y-27632. Results: Diabetes triggered BRB breakdown and caused significant increases in circulatory and retinal TNF-α and IL-1β levels. These effects coincided with significant decreases in retinal NGF and increases in vascular endothelial growth factor and proNGF expression, as well as activation of RhoA. Interventional modulation of p75NTR activity through treatment of mouse models of diabetes with LM11A-31 significantly mitigated proNGF accumulation and preserved BRB integrity. In HRE cells, treatment with mutant proNGF (10 ng/ml) triggered increased cell permeability with marked reduction of expression of tight junction proteins, zona occludens-1 (ZO-1) and claudin-5, compared with control, independent of inflammatory mediators or cell death. Modulating p75NTR significantly inhibited proNGF-mediated RhoA activation, occludin phosphorylation (at serine 490) and cell permeability. ProNGF induced redistribution of ZO-1 in the cell wall and formation of F-actin stress fibres; these effects were mitigated by LM11A-31. Conclusions/interpretation: Targeting p75NTR signalling using LM11A-31, an orally bioavailable receptor modulator, may offer an effective, safe and non-invasive therapeutic strategy for treating macular oedema, a major cause of blindness in diabetes.
The p75 neurotrophin receptor inhibitor, LM11A-31, ameliorates acute stroke injury and modulates astrocytic proNGF
Exp Neurol 2023 Jan;359:114161.PMID:35787888DOI:10.1016/j.expneurol.2022.114161.
The precursor form of nerve growth factor (proNGF) is essential to maintain NGF survival signaling. ProNGF is also among endogenous ligands for p75 neurotrophin receptor (p75ntr). Mounting evidence implies that p75ntr signaling contributes to neural damage in ischemic stroke. The present study examines the therapeutic effect of the p75ntr modulator LM11A-31. Adult mice underwent transient distal middle cerebral artery occlusion (t-dMCAO) followed by LM11A-31 treatment (25 mg/kg, i.p., twice daily) either for 72 h post-injury (acute phase) or afterward till two weeks post-stroke (subacute phase). LM11A-31 reduced blood-brain barrier permeability, cerebral tissue injury, and sensorimotor function in the acute phase of stroke. Ischemic brain samples showed repressed proNGF/P75ntr signaling and Caspase 3 activation in LM11A-31 treated mice, where we observed less reactive microglia and IL-1β production. LM11A-31 (20-80 nM) also mitigated neural injury induced by oxygen-glucose deprivation (OGD) in sandwich co-cultures of primary cortical neurons (PCN) and astrocytes. This concurred with JNK/PARP downregulation and reduced caspase-3 cleavage in the PCNs and was associated with repressed proNGF generation in astrocytes. Further in vitro experiments indicated human proNGF suppresses the pro-inflammatory phenotype in microglial cultures, as determined by a sharp decline in HMGB-1 production and moderate arginase-1 upregulation. Despite significant protection in acute stroke, LM11A-31 treatment did not improve cortical atrophy and sensorimotor function in the subacute phase. Our findings provide preclinical evidence supporting LM11A-31 as a promising therapy for acute stroke injury. Further investigations may elucidate if reduced astrocytic proNGF, an endogenous reservoir of pro-neurotrophins, may restrict the therapeutic window.
Improved neurocognitive performance in FIV infected cats following treatment with the p75 neurotrophin receptor ligand LM11A-31
J Neurovirol 2021 Apr;27(2):302-324.PMID:33661457DOI:10.1007/s13365-021-00956-2.
HIV rapidly infects the central nervous system (CNS) and establishes a persistent viral reservoir within microglia, perivascular macrophages and astrocytes. Inefficient control of CNS viral replication by antiretroviral therapy results in chronic inflammation and progressive cognitive decline in up to 50% of infected individuals with no effective treatment options. Neurotrophin based therapies have excellent potential to stabilize and repair the nervous system. A novel non-peptide ligand, LM11A-31, that targets the p75 neurotrophin receptor (p75NTR) has been identified as a small bioavailable molecule capable of strong neuroprotection with minimal side effects. To evaluate the neuroprotective effects of LM11A-31 in a natural infection model, we treated cats chronically infected with feline immunodeficiency virus (FIV) with 13 mg/kg LM11A-31 twice daily over a period of 10 weeks and assessed effects on cognitive functions, open field behaviors, activity, sensory thresholds, plasma FIV, cerebrospinal fluid (CSF) FIV, peripheral blood mononuclear cell provirus, CD4 and CD8 cell counts and general physiology. Between 12 and 18 months post-inoculation, cats began to show signs of neural dysfunction in T maze testing and novel object recognition, which were prevented by LM11A-31 treatment. Anxiety-like behavior was reduced in the open field and no changes were seen in sensory thresholds. Systemic FIV titers were unaffected but treated cats exhibited a log drop in CSF FIV titers. No significant adverse effects were observed under all conditions. The data indicate that LM11A-31 is likely to be a potent adjunctive treatment for the control of neurodegeneration in HIV infected individuals.