Anti-ceramidase LCL385 acutely reduces BCL-2 expression in the hippocampus but is not associated with an increase of learned helplessness in rats

Nahas, Ziad; Jiang, Yan; Zeidan, Youssef H.; Bielawska, Alicja; Szulc, Zdzisław M.; DeVane, Lindsay; Kalivas, Peter W.; Hannun, Yusuf A.

doi:10.1016/j.bbr.2008.07.040

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…However, cell life and death may be of limited importance for provocation of behavioral despair in the rat forced swim test. Treatment of rats with pro-apoptotic compound, LCL385, did not affect immobility in this test (Nahas et al 2009). Therefore, Bcl-xL expression may contribute to psychobiological resilience to stress-induced depression-like state through other than apoptotic mechanisms such as, for example, by increasing energy supply in the neuron and by modulating density and function of synapses.…”

Section: Mechanisms Of the Bcl-xl Effects On Behavioral Resilience Tomentioning

confidence: 94%

Increased Expression of the Anti-Apoptotic Protein Bcl-xL in the Brain is Associated with Resilience to Stress-Induced Depression-Like Behavior

et al. 2012

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Clinical observations and the results of animal studies have implicated changes in neuronal survival and plasticity in both the etiology of mood disorders, especially stress-induced depression, and anti-depressant drug action. Stress may predispose individuals toward depression through down-regulation of neurogenesis and an increase in apoptosis in the brain. Substantial individual differences in vulnerability to stress are evident in humans and were found in experimental animals. Recent studies revealed an association between the brain anti-apoptotic protein B cell lymphoma like X, long variant (Bcl-xL) expression and individual differences in behavioral vulnerability to stress. The ability to increase Bcl-xL gene expression in the hippocampus in response to stress may be an important factor for determining the resistance to the development of stress-induced depression. Treatment with anti-depressant drugs may change Bcl-xL response properties. In the rat brainstem, expression of this anti-apoptotic gene becomes sensitive to swim stress during the long-term fluoxetine treatment, an effect that appeared concomitantly with the anti-depressant-like action of the drug in the forced swim test, suggesting that Bcl-xL may be a new target for depression therapy. The processes and pathways linking stress stimuli to behavior via intracellular anti-apoptotic protein are discussed here in the context of Bcl-xL functions in the mechanisms of individual differences in behavioral resilience to stress and anti-depressant-induced effects on the behavioral despair.

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Section: Mechanisms Of the Bcl-xl Effects On Behavioral Resilience Tomentioning

confidence: 94%

Increased Expression of the Anti-Apoptotic Protein Bcl-xL in the Brain is Associated with Resilience to Stress-Induced Depression-Like Behavior

et al. 2012

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“…Our group has been focusing on the development of ACDase inhibitors for many years. Based on substrate similarity, a diverse set of compounds established on the structural skeleton of phenyl amino alcohol were designed and validated [ 9 – 13 ]. Among them, B13, (1R, 2R)-1-(4’-nitrophenyl)-2-(tetradecanoyl-amido)-1, 3-propandiol, was identified as a potent ACDase inhibitor in vitro .…”

Section: Introductionmentioning

confidence: 99%

Anticancer actions of lysosomally targeted inhibitor, LCL521, of acid ceramidase

et al. 2017

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Acid ceramidase, which catalyzes ceramide hydrolysis to sphingosine and free fatty acid mainly in the lysosome, is being recognized as a potential therapeutic target for cancer. B13 is an effective and selective acid ceramidase inhibitor in vitro, but not as effective in cells due to poor access to the lysosomal compartment. In order to achieve targeting of B13 to the lysosome, we designed lysosomotropic N, N-dimethyl glycine (DMG)-conjugated B13 prodrug LCL521 (1,3-di-DMG-B13). Our previous results indicated the efficient delivery of B13 to the lysosome resulted in augmented effects of LCL521 on cellular acid ceramidase as evaluated by effects on substrate/product levels. Our current studies indicate that functionally, this translated into enhanced inhibition of cell proliferation. Moreover, there were greater synergistic effects of LCL521 with either ionizing radiation or Tamoxifen. Taken together, these results clearly indicate that compartmental targeting for the inhibition of acid ceramidase is an efficient and valuable therapeutic strategy.

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“…Some of these drugs are also active in vivo [100]. A systematic investigation of drug-like non-lipid functional inhibitors of AC is completely lacking so far.…”

Section: Inhibition Of Acmentioning

confidence: 99%

Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications

Kornhuber¹,

Tripal²,

Reichel³

et al. 2010

Cell Physiol Biochem

314

348

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Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer’s disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym “FIASMA” (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM.

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Anti-ceramidase LCL385 acutely reduces BCL-2 expression in the hippocampus but is not associated with an increase of learned helplessness in rats

Cited by 12 publications

References 24 publications

Increased Expression of the Anti-Apoptotic Protein Bcl-xL in the Brain is Associated with Resilience to Stress-Induced Depression-Like Behavior

Increased Expression of the Anti-Apoptotic Protein Bcl-xL in the Brain is Associated with Resilience to Stress-Induced Depression-Like Behavior

Anticancer actions of lysosomally targeted inhibitor, LCL521, of acid ceramidase

Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications

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