Inhibition of neutral sphingomyelinase 2 reduces extracellular vesicle release from neurons, oligodendrocytes, and activated microglial cells following acute brain injury

Tallon, Carolyn; Picciolini, Silvia; Yoo, Seung‐Wan; Thomas, Ajit G.; Pal, Arindom; Alt, Jesse; Carlomagno, Cristiano; Gualerzi, Alice; Rais, Rana; Haughey, Norman J.; Bedoni, Marzia; Slusher, Barbara S.

doi:10.1016/j.bcp.2021.114796

Cited by 26 publications

(25 citation statements)

References 71 publications

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“…This indicates that in order for there to be inhibitory effects, there needs to be an increase in nSMase2 activity driven by inflammation as a result of pathology, thus leading to targeted D-DPTIP localization. This is further substantiated by nSMase2 activity levels increasing in response to an inflammatory insult in our acute brain injury model ( Figure 4 B,C), as well as nSMase2 inhibition leading to reduced inflammatory markers of microglia [ 58 , 78 ], thus demonstrating a link between inflammation and nSMase2 activity.…”

Section: Discussionsupporting

confidence: 71%

“…Plasma EVs and isolated GFP+ EVs from the IL-1β EV release mouse model were quantified using the ZetaView Nanoparticle Tracker (Particle Metrix GmBH, Meerbusch, Germany) corresponding ZetaView software (8.05.14.SP7) as previously described [ 27 , 58 ]. Briefly, 1 mL of 10,000× g centrifuged plasma was injected into the sample-carrier cell and the particle count was measured at five different positions with two cycles of reading at each position.…”

Section: Methodsmentioning

confidence: 99%

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Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

et al. 2022

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Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

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Section: Discussionsupporting

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

et al. 2022

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“…Many published reports have identified roles for nSMase2-generated ceramide in regulating glial activation, myelination, neuronal plasticity, and cell survival. − The nSMase2-generated ceramide regulates cellular signaling largely through modulation of the biophysical properties of cellular membranes. Ceramides pack tightly together and are critical components of highly ordered membrane microdomains. , These domains, also known as lipid rafts, are highly dynamic structures that serve to regulate signaling by controlling the localization and activation of membrane receptors and their association with secondary signal transduction machinery. , The nSMase2-generated ceramide also regulates cellular signaling by regulating the biogenesis of at least one population of extracellular vesicles (EVs). , …”

Section: Introductionmentioning

confidence: 99%

“…10,11 The nSMase2-generated ceramide also regulates cellular signaling by regulating the biogenesis of at least one population of extracellular vesicles (EVs). 12,13 EVs are small vesicular carriers shed from cells that contain a variety of cargo including proteins, nucleic acids, miRNAs, and bioactive lipids. The cargo of EVs is modified by the stimulus used to evoke their release.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Orally Bioavailable and Brain-Penetrable Prodrugs of the Potent nSMase2 Inhibitor DPTIP

Pal

Gori

Yoo³

et al. 2022

J. Med. Chem.

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Extracellular vesicles (EVs) can carry pathological cargo and play an active role in disease progression. Neutral sphingomyelinase-2 (nSMase2) is a critical regulator of EV biogenesis, and its inhibition has shown protective effects in multiple disease states. 2,6-Dimethoxy-4-(5-phenyl-4-thiophen-2yl-1H-imidazol-2-yl)phenol (DPTIP) is one of the most potent (IC 50 = 30 nM) inhibitors of nSMase2 discovered to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), limiting its clinical development. To overcome DPTIP's PK limitations, we synthesized a series of prodrugs by masking its phenolic hydroxyl group. When administered orally, the best prodrug (P18) with a 2′,6′-diethyl-1,4′-bipiperidinyl promoiety exhibited >fourfold higher plasma (AUC 0−t = 1047 pmol•h/mL) and brain exposures (AUC 0−t = 247 pmol•h/g) versus DPTIP and a significant enhancement of DPTIP half-life (2 h vs ∼0.5 h). In a mouse model of acute brain injury, DPTIP released from P18 significantly inhibited IL-1β-induced EV release into plasma and attenuated nSMase2 activity. These studies report the discovery of a DPTIP prodrug with potential for clinical translation.

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“…All the aforementioned types of cells have been found to naturally secrete EVs under normal, physiological, and pathological conditions, owing to the dynamics of the cell membrane ( Zhang et al, 2021a ; Forró et al, 2021 ). A great deal of evidence has demonstrated that EVs derived from these cells exert biological functions by modulating specific aspects, such as participation in inflammatory reactions, cell migration, proliferation, apoptosis, and autophagy ( Gao et al, 2020 ; Zhang et al, 2021a ; Tallon et al, 2021 ). However, data on the precise mechanisms underlying such a therapeutic approach are limited.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke

Kang

Xin

et al. 2022

Front. Pharmacol.

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Neurons and neurogliocytes (oligodendrocytes, astrocytes, and microglia) are essential for maintaining homeostasis of the microenvironment in the central nervous system (CNS). These cells have been shown to support cell-cell communication via multiple mechanisms, most recently by the release of extracellular vesicles (EVs). Since EVs carry a variety of cargoes of nucleic acids, lipids, and proteins and mediate intercellular communication, they have been the hotspot of diagnosis and treatment. The mechanisms underlying CNS disorders include angiogenesis, autophagy, apoptosis, cell death, and inflammation, and cell-EVs have been revealed to be involved in these pathological processes. Ischemic stroke is one of the most common causes of death and disability worldwide. It results in serious neurological and physical dysfunction and even leads to heavy economic and social burdens. Although a large number of researchers have reported that EVs derived from these cells play a vital role in regulating multiple pathological mechanisms in ischemic stroke, the specific interactional relationships and mechanisms between specific cell-EVs and stroke treatment have not been clearly described. This review aims to summarize the therapeutic effects and mechanisms of action of specific cell-EVs on ischemia. Additionally, this study emphasizes that these EVs are involved in stroke treatment by inhibiting and activating various signaling pathways such as ncRNAs, TGF-β1, and NF-κB.

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Inhibition of neutral sphingomyelinase 2 reduces extracellular vesicle release from neurons, oligodendrocytes, and activated microglial cells following acute brain injury

Cited by 26 publications

References 71 publications

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

Discovery of Orally Bioavailable and Brain-Penetrable Prodrugs of the Potent nSMase2 Inhibitor DPTIP

The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke

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