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Sci Rep. 2018 Dec 7;8(1):17715. doi: 10.1038/s41598-018-36144-2.

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

Author information

1
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
2
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
3
National Center for Advancing Translational Sciences (NCATS), National Institute of Health, Bethesda, MD, 20892-3370, USA.
4
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA.
5
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. nhaughe1@jhmi.edu.
6
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. marc.ferrer@nih.gov.
7
Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.
8
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.
9
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.
10
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.
11
Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.
12
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, 21205, USA. bslusher@jhmi.edu.

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 (IC50 ≥ 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 (IC50 30 nM), selective, metabolically stable, and brain penetrable (AUCbrain/AUCplasma = 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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