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Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways.
For research use only. We do not sell to patients.
Delayed administration of Necrosulfonamide (NSA) reduces the protein level of RIP3K or MLKL and GFAP after OGD/Re injury. Astrocytes are exposed to OGD for 6 h followed by reoxygenation for 24 h. NSA (1 μM) is added to the cells upon reoxygenation.
Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways[1][2][3][4][5][6][7].
Necrosulfonamide (0-10 μM) blocks necrosis in both human colon cancer HT-29 cells and FADD null human T cell leukemia Jurkat cells with IC50s both less than 1 μM, but it has no effect on mouse cells, for that the cysteine at the 86th position in human MLK1 is replaced by tryptophan in the mouse MLKL after covalent modification[1].
Necrosulfonamide (6 h) acts downstream of RIP3 activation, it does not inhibit the interaction or phosphorylation between RIP1 and RIP3; but enhances these processes in RIP3-HT-29 cells[1].
Necrosulfonamide (10 μM, 45 min-25 h) inhibits the release of inflammatory factors and pyroptosis in BMDMs and NCM460 cells necroptosis and has no effect on the vitality of the two types of cells[4].
Necrosulfonamide (0.1-100 μM) protects primary cultured astrocytes and human astrocytes against oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced cell injury, reduces the number of PI-positive cells and inhibits the levels of necroptosis-related proteins[5].
Necrosulfonamide (0.1-1 μM, 6 h) reverses pyroptosis-induced inhibition of proliferation and differentiation of osteoblasts through the NLRP3/caspase-1/GSDMD pathway in hFOB 1.19 cells[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Inhibited the activation of the pyroptosis execution proteins (caspase-1, GSDMD).
Increased the protein expressions of key osteogenic markers (ALP, Runx2, COL-1, OPN, BMP-2)
Reduced the levels of IL-6, TNF-α and IL-1β in the cell supernatant
In Vivo
Necrosulfonamide (20 mg/kg, i.p., single dose) alleviates Lipopolysaccharide (HY-D1056A1)/D-galactosamine (HY-42682)-induced acute liver failure in mice[2].
Necrosulfonamide (1-5 mg/kg, i.p., once daily for 3 days) reduces oxidative Stress, inflammation, and dopaminergic neuronal cell death in MPTP (HY-15608)-induced Parkinson’s disease mouse model[3].
Necrosulfonamide (20-40 mg/kg, i.p., once other daily for 5-7 days) ameliorates Inflammatory bowel disease (IBD) in mice via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis[4].
Necrosulfonamide (40-80 nmol, intracerebroventricular administration, single dose) produces neuroprotective effects against ischemia/reperfusion (I/R)-induced acute brain injury in rats[5].
Necrosulfonamide promotes hair growth and prevents hair follicle degeneration in androgenetic alopecia (AGA) mice through Wnt signaling[7].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
LPS/D-galactosamine-induced acute liver failure established in male 8-week-old specific pathogen-free (SPF) grade C57BL/6J mice[2]
Dosage:
20 mg/kg
Administration:
Intraperitoneal injection (i.p.), single dose before the model creation process
Result:
Increased the survival rate of mice, reduced the serum ALT level, and alleviated liver tissue damage.
Reduced the levels of serum IL-1β and IL-18.
Downregulated the protein levels of NLRP3, cleaved caspase-1, cleaved caspase-11, and mature IL-1β.
Animal Model:
MPTP-induced Parkinson’s disease mouse model established in male C57BL/6 mice (24-25 g, 9-10 weeks old)[3]
Dosage:
1 and 5 mg/kg
Administration:
Intraperitoneal injection (i.p.), single dose before the model creation process
Result:
Reduced the death of dopaminergic neurons and restores neurotrophic factors.
Reduced the levels of pro-inflammatory mediators such as iNOS, TNF-α, IL-1β, and IL-6.
Reduced the activation of microglial cells and astrocytes in the substantia nigra and striatum.
Restored the expression of the core antioxidant transcription factor Nrf2 and a series of downstream antioxidant enzymes (HO-1, catalase, MnSOD, GCLC, GCLM).
Effectively inhibited the expression of p-MLKL and MLKL, and reduced the number of p-MLKL+/TH+ and p-MLKL+/OX-42+ cells.
Animal Model:
DSS (HY-116282C) induced IBD model established in male 6- to 9-week-old C57BL/6 mice weighting 22-26 g [4]
Dosage:
20 and 40 mg/kg (prevent) and 20 mg/kg (treatment)
Administration:
Intraperitoneal injection (i.p.), once every other day for 7 days (prevent) and for 5 days (treatment)
Result:
Significantly reduced the DAI score and increased the colon length in a dose-dependent manner.
Reduced the levels of serum TNF-α and MPO.
Reduced the inflammatory score, retained more goblet cells and mucus layers, and decreased the infiltration of CD4+ T cells, CD8+ T cells and macrophages (F4/80+) in the colon tissue.
Reduced the levels of 16sRNA, IL-1β, TNF-α, and IL-6 mRNA, inhibited p-p65, and promoted Nrf2 expression.
Reduced the death of colonic epithelial cells and p-MLKL-positive cells, and inhibited the expression of necroptosis markers (p-MLKL, p-RIPK1, p-RIPK3) and pyroptosis markers (N-GSDMD).
Animal Model:
Transient middle cerebral artery occlusion model established in adult male SD rats (290-310 g)[5]
Dosage:
40 and 80 nmol
Administration:
Intracerebroventricular administration, single dose
Result:
Significantly reduced the volume of cerebral infarction.
Significantly improved the neurological function score and the asymmetry of forelimb usage.
Significantly reduced the number of PI-positive cells.
Inhibited the total expression levels of MLKL/p-MLKL, RIP3K/p-RIP3K, and RIP1K/p-RIP1K in the ischemic penumbra tissue, and translocation of MLKL/p-MLKL and RIP3K/p-RIP3K to the nucleus and nuclear membrane.
Room temperature in continental US; may vary elsewhere.
Storage
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
2 years
-20°C
1 year
Solvent & Solubility
In Vitro:
DMSO : ≥ 28 mg/mL (60.68 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
*"≥" means soluble, but saturation unknown.
Preparing Stock Solutions
ConcentrationSolventMass
1 mg
5 mg
10 mg
1 mM
2.1670 mL
10.8349 mL
21.6699 mL
5 mM
0.4334 mL
2.1670 mL
4.3340 mL
10 mM
0.2167 mL
1.0835 mL
2.1670 mL
View the Complete Stock Solution Preparation Table
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.
For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day. The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Solubility: 2.5 mg/mL (5.42 mM); Suspended solution; Need ultrasonic
This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Protocol 2
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: 2.5 mg/mL (5.42 mM); Suspended solution; Need ultrasonic
This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Protocol 3
Add each solvent one by one: 10% DMSO 90% Corn Oil
Solubility: 2.5 mg/mL (5.42 mM); Suspended solution; Need ultrasonic
This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 900 μLCorn oil, and mix evenly.
For the following dissolution methods, please prepare the working solution directly.
It is recommended to prepare fresh solutions and use them promptly within a short period of time. The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution.
If precipitation or phase separation occurs during preparation,
heat and/or sonication can be used to aid dissolution.
Protocol 1
Add each solvent one by one: 50% PEG300 50% Saline
Solubility: 10 mg/mL (21.67 mM); Suspended solution; Need ultrasonic
Protocol 2
Add each solvent one by one: 20% SBE-β-CD in Saline
Solubility: 6.67 mg/mL (14.45 mM); Suspended solution; Need ultrasonic
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
Dosage
mg/kg
Animal weight (per animal)
g
Dosing volume (per animal)
μL
Number of animals
Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO+
%
+
%
Tween-80
+
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO,
. All of co-solvents are available by MedChemExpress (MCE).
, Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration:
mg/mL
Method for preparing stock solution:
mg
drug dissolved in
μL
DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take
μL DMSO stock solution, add
μL .
μL , mix evenly, next add
μL Tween 80, mix evenly, then add
μL Saline.
Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution
If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.
Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.
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