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].
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)
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.
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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