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| Targets |
- The target of LM22A-4 is the tropomyosin receptor kinase B (TrkB) receptor (brain-derived neurotrophic factor, BDNF, mimetic receptor). [1]
- The target of LM22A-4 is the TrkB receptor; it activates the TrkB-mediated signaling pathway to regulate cell differentiation. [2] |
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| ln Vitro |
LM22A-4 dramatically raised OPN and ALPase mRNA expression in a dose-dependent manner, while 5 μM LM22A-4 significantly enhanced OC mRNA levels. LM22A-4 significantly boosted OPN, ALPase, and OC mRNA expression in a time-dependent manner. LM22A-4 promotes OPN and OC mRNA expression in HCEM cells grown with mineralized media [2].
- In rat pheochromocytoma (PC12) cells induced to differentiate into neuron-like cells, LM22A-4 (1, 10, 20 μM) dose-dependently reduced cell apoptosis induced by H₂O₂ (200 μM). At 20 μM, it increased the anti-apoptotic protein Bcl-2 expression by 2.3-fold and decreased the pro-apoptotic protein Bax expression by 0.4-fold compared with the H₂O₂-treated group. It also upregulated TrkB protein expression by 1.8-fold and promoted neurite outgrowth (neurite length increased by 1.6-fold at 20 μM) [1] - In mouse cementoblast-like cells (OCCM-30), LM22A-4 (1, 5, 10 μM) dose-dependently promoted cell differentiation. At 10 μM, it increased alkaline phosphatase (ALP) activity by 2.5-fold, enhanced mineralized nodule formation (number of nodules increased by 2.1-fold), and upregulated the mRNA expression of osteogenic differentiation markers: runt-related transcription factor 2 (Runx2) by 3.0-fold and osterix (OSX) by 2.8-fold. It also activated the TrkB-ERK/Akt signaling cascade: at 10 μM, it increased the phosphorylation levels of TrkB (p-TrkB) by 2.7-fold, extracellular signal-regulated kinase (p-ERK) by 2.4-fold, and protein kinase B (p-Akt) by 2.2-fold compared with the control group [2] |
| ln Vivo |
LM22A-4 (10 mg/kg, intraperitoneally) dramatically decreased the degree of tissue damage and apoptosis (as measured by TUNEL staining, caspase-3, and Bcl-2 expression) as compared to the vehicle-treated group. Additionally, recovery of limb function was greatly enhanced by LM22A-4. The number of neurons increased significantly after treatment with LM22A-4 (10 mg/kg). When LM22A-4 (10 mg/kg) was administered to mice, their neurological scores dramatically improved in comparison to animals that were treated with solvents [1].
- In a rat spinal cord contusion injury (SCI) model: After SCI induction, LM22A-4 (10 mg/kg) was administered intraperitoneally once daily for 7 consecutive days, starting 1 hour post-injury. At 28 days post-injury, the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale score (evaluating hindlimb motor function) in the LM22A-4-treated group was 12.3 ± 1.5, significantly higher than the vehicle control group (6.2 ± 1.1). Histological analysis showed that the number of surviving neurons in the injured spinal cord segment (T10) was 45.6 ± 5.2 per high-power field (HPF) in the treatment group, compared with 21.3 ± 3.8 in the control group; the myelin sheath area was also increased by 58% in the treatment group [1] |
| Enzyme Assay |
- For TrkB signaling activation assay in OCCM-30 cells: Cells were seeded in 6-well plates and cultured until 80% confluence, then serum-starved for 12 hours. Cells were treated with LM22A-4 (10 μM) for 0, 15, 30, 60, and 120 minutes. After treatment, cells were lysed with RIPA buffer containing protease and phosphatase inhibitors. The lysates were centrifuged at 12,000 × g for 15 minutes at 4°C to collect the supernatant. Protein concentration was determined using a BCA assay kit. Equal amounts of protein were separated by SDS-PAGE and transferred to PVDF membranes. Membranes were blocked with 5% non-fat milk for 1 hour at room temperature, then incubated with primary antibodies against p-TrkB, TrkB, p-ERK, ERK, p-Akt, and Akt overnight at 4°C. After washing with TBST, membranes were incubated with horseradish peroxidase (HRP)-conjugated secondary antibodies for 1 hour at room temperature. Bands were visualized using an ECL detection system, and band intensity was quantified using image analysis software [2]
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| Animal Protocol |
- For rat spinal cord contusion injury (SCI) model: Adult male Sprague-Dawley rats (250–300 g) were used to establish the SCI model by contuding the T10 spinal segment with a weight-drop device (10 g weight dropped from a height of 5 cm). Rats were randomly divided into two groups: LM22A-4 treatment group and vehicle control group (n=8/group). LM22A-4 was dissolved in 0.9% normal saline containing 0.1% DMSO to a concentration of 2 mg/mL. The treatment group received intraperitoneal injection of LM22A-4 at 10 mg/kg once daily, starting 1 hour after SCI, and continued for 7 consecutive days. The control group received the same volume of 0.9% normal saline containing 0.1% DMSO. Hindlimb motor function was evaluated using the BBB scale at 1, 7, 14, 21, and 28 days post-injury. At 28 days post-injury, rats were sacrificed, and the T10 spinal segment was harvested. The spinal tissue was fixed with 4% paraformaldehyde, embedded in paraffin, sectioned (5 μm), and stained with hematoxylin-eosin (HE) and Luxol fast blue (LFB) to observe neuron survival and myelin sheath integrity, respectively [1]
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| References | |
| Additional Infomation |
LM22A-4 is a small molecule BDNF mimic compound that can exert neuroprotective effects by activating TrkB receptors. Its protective effect on damaged spinal cord nerves is mainly achieved by inhibiting neuronal apoptosis, promoting neurite growth and maintaining the integrity of spinal cord tissues [1]. - LM22A-4 regulates cementum cell differentiation through the TrkB-ERK/Akt signaling pathway, which is of great significance for repairing periodontal tissue defects (such as alveolar bone loss) by promoting cementum formation [2].
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| Molecular Formula |
C15H21N3O6
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|---|---|
| Molecular Weight |
339.34374
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| Exact Mass |
339.143
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| CAS # |
37988-18-4
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| PubChem CID |
2054170
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| Appearance |
White to off-white solid powder
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| LogP |
-2.3
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
24
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| Complexity |
358
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RGWJKANXFYJKHN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H21N3O6/c19-4-1-16-13(22)10-7-11(14(23)17-2-5-20)9-12(8-10)15(24)18-3-6-21/h7-9,19-21H,1-6H2,(H,16,22)(H,17,23)(H,18,24)
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| Chemical Name |
1-N,3-N,5-N-tris(2-hydroxyethyl)benzene-1,3,5-tricarboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ≥ 50 mg/mL (~147.34 mM)
DMSO : ≥ 29 mg/mL (~85.46 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 120 mg/mL (353.63 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9469 mL | 14.7345 mL | 29.4690 mL | |
| 5 mM | 0.5894 mL | 2.9469 mL | 5.8938 mL | |
| 10 mM | 0.2947 mL | 1.4734 mL | 2.9469 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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