TY  - JOUR
A1  - Naser, Eyad
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Mohamed, Zainelabdeen H.
A1  - Kappe, Christian
A1  - Hessler, Gabriele
A1  - Pollmeier, Barbara
A1  - Kleuser, Burkhard
A1  - Arenz, Christoph
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Characterization of the small molecule ARC39
BT  - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
JF  - Journal of Lipid Research
N2  - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
KW  - sphingolipids
KW  - sphingomyelin
KW  - cerami-des
KW  - lipid metabolism
KW  - enzymology
KW  - lysosome
KW  - lysosomal hydrolases
KW  - acid ceramidase
KW  - bisphosphonates
KW  - functional inhibitors of acid sphin-gomyelinase
KW  - 1-aminodecylidene bis-phosphonic acid
Y1  - 2021
U6  - https://doi.org/10.1194/jlr.RA120000682
SN  - 1539-7262
SN  - 0022-2275
VL  - 61
IS  - 6
SP  - 896
EP  - 910
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Huston, Joseph P.
A1  - Kornhuber, Johannes
A1  - Muehle, Christiane
A1  - Japtok, Lukasz
A1  - Komorowski, Mara
A1  - Mattern, Claudia
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Kleuser, Burkhard
A1  - Topic, Bianca
A1  - Silva, Maria A. De Souza
A1  - Mueller, Christian P.
T1  - A sphingolipid mechanism for behavioral extinction
JF  - Journal of neurochemistry
N2  - Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - extinction
KW  - hippocampus
KW  - operant behavior
KW  - sphingomyelin
Y1  - 2016
U6  - https://doi.org/10.1111/jnc.13537
SN  - 0022-3042
SN  - 1471-4159
VL  - 137
SP  - 589
EP  - 603
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -