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DPTIP, a newly identified potent brain penetrant neutral sphingomyelinase 2 inhibitor, regulates astrocyte-peripheral immune communication following brain inflammation. | LitMetric

AI Article Synopsis

  • Brain injury and inflammation lead to the release of extracellular vesicles (EVs) from astrocytes, which can trigger immune responses that worsen brain damage and hinder recovery.
  • Inhibiting the enzyme neutral sphingomyelinase 2 (nSMase2) may offer a new treatment method, but existing inhibitors have limitations like low effectiveness and poor brain entry.
  • A new compound, DPTIP, was found to be a strong and effective nSMase2 inhibitor that reduced EV release and related immune responses in mouse models of brain injury, showing potential for better therapeutic outcomes.

Article Abstract

Brain injury and inflammation induces a local release of extracellular vesicles (EVs) from astrocytes carrying proteins, RNAs, and microRNAs into the circulation. When these vesicles reach the liver, they stimulate the secretion of cytokines that mobilize peripheral immune cell infiltration into the brain, which can cause secondary tissue damage and impair recovery. Recent studies suggest that suppression of EV biosynthesis through neutral sphingomyelinase 2 (nSMase2) inhibition may represent a new therapeutic strategy. Unfortunately, currently available nSMase2 inhibitors exhibit low potency (IC ≥ 1 μM), poor solubility and/or limited brain penetration. Through a high throughput screening campaign of >365,000 compounds against human nSMase2 we identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), a potent (IC 30 nM), selective, metabolically stable, and brain penetrable (AUC/AUC = 0.26) nSMase2 inhibitor. DPTIP dose-dependently inhibited EV release in primary astrocyte cultures. In a mouse model of brain injury conducted in GFAP-GFP mice, DPTIP potently (10 mg/kg IP) inhibited IL-1β-induced astrocyte-derived EV release (51 ± 13%; p < 0.001). This inhibition led to a reduction of cytokine upregulation in liver and attenuation of the infiltration of immune cells into the brain (80 ± 23%; p < 0.01). A structurally similar but inactive analog had no effect in vitro or in vivo.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286365PMC
http://dx.doi.org/10.1038/s41598-018-36144-2DOI Listing

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