Phospholipase A2 is involved in galactosylsphingosine-induced astrocyte toxicity, neuronal damage and demyelination

Misslin, Cedric; Velasco‐Estevez, María; Albert, Marie; O’Sullivan, Sinead A.; Dev, Kumlesh K.

doi:10.1371/journal.pone.0187217

Cited by 21 publications

(40 citation statements)

References 60 publications

(89 reference statements)

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“…On the contrary, treatment of slices with 500 nM GsMTx4 promoted PLP expression in slice cultures. As previously described by Misslin et al (2017), 18 hr exposure to 100 nM psychosine (PSY) induced demyelination. However, co-treatment of slices with PSY + GsMTx4 prevented demyelination.…”

Section: Piezo1 Is Expressed By Neurons In the Mouse Brainmentioning

confidence: 77%

“…Exposure to Yoda‐1 or psychosine caused similar levels of demyelination (Figure g). We have previously reported that psychosine induces demyelination of organotypic cerebellar slices (Misslin et al, ; O'Sullivan & Dev, ) and have used this system as an ex vivo model of the dysmyelination that occurs in Krabbe disease (Giri et al, ). Importantly, blocking Piezo1 channels with GsMTx4 prevented psychosine‐mediated demyelination.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we examined whether blocking Piezo1 channels prevents the axonal damage that often accompanies demyelination. Slices were once again treated using the same protocol described in Figure f and then fixed and stained for SMI‐32, a nonphosphorylated epitope of NFH (Louis et al, ) and a marker of axonal damage and demyelination (Lindner, Fokuhl, Linsmeier, Trebst, & Stangel, ; Misslin et al, ; O'Sullivan, Velasco‐Estevez, & Dev, ). Organotypic cerebellar slices treated with the Piezo1 activator, Yoda‐1 (10 μM for 48 hr), displayed an increase in SMI‐32 expression in the axons of cerebellar Purkinje neurons (Figure a,b).…”

Section: Resultsmentioning

confidence: 99%

“…Galactosylsphingosine or psychosine (Santa Cruz Biotechnology, sc-202781) is a cationic lysosphingolipid that accumulates in the brains of patients with Krabbe disease (Giri et al, 2002) and causes oligodendrocyte cell death and demyelination (Misslin, Velasco-Estevez, Albert, O'Sullivan, & Dev, 2017;O'Sullivan & Dev, 2015).…”

Section: Reagentsmentioning

confidence: 99%

“…* represents a statistically significant difference (p < .05) from control and # represents a statistically significant difference (p < .05) between psychosine and PSY + GsMTx4 groups [Color figure can be viewed at wileyonlinelibrary.com] demyelination (Figure 2g). We have previously reported that psychosine induces demyelination of organotypic cerebellar slices (Misslin et al, 2017;O'Sullivan & Dev, 2015) and have used this system as an ex vivo model of the dysmyelination that occurs in Krabbe disease (Giri et al, 2002). Importantly, blocking Piezo1 channels with GsMTx4 prevented psychosine-mediated demyelination.…”

Section: Blocking Mechanosensitive Ion Channels Enhances Myelinatiomentioning

confidence: 99%

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Inhibition of Piezo1 attenuates demyelination in the central nervous system

Velasco‐Estevez

Gadalla

Liñan-Barba

et al. 2019

Glia

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Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases.

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Section: Piezo1 Is Expressed By Neurons In the Mouse Brainmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

Section: Blocking Mechanosensitive Ion Channels Enhances Myelinatiomentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Velasco‐Estevez

Gadalla

Liñan-Barba

et al. 2019

Glia

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The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease

Papakyriakopoulou,

Valsami,

Dev

2024

Mol Neurobiol

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Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

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Low Vs. High Alcohol: Central Benefits Vs. Detriments

et al. 2018

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The dose-dependent effects of alcohol, where the initial euphoric and stimulant effects initiated by the exposure to low ethanol levels can quickly lead to a deadly consequence are well established. Thus, high blood alcohol concentration (BAC), as seen in alcoholics, can cause significant damage to various organs. At low concentrations (e.g., 10 mg% or lower), however, beneficial effects of alcohol, particularly on cardiovascular function have been reported. Although, the latter assertion has been challenged by recent epidemiological studies, protective effects of low alcohol concentrations in vitro and in vivo relevant to the central nervous system (CNS) is well documented. In this review, the mechanism(s) leading to the detrimental effects of high BAC, as well as the beneficial effects of low BAC will be discussed. In addition, gender consideration is touched upon. Although further investigation is clearly warranted, it may be concluded that at least some of the beneficial outcomes of low BAC, including possible neuroprotection and antidepressant-like effects, may be due to elevation of the neurotropic factors and reduction of inflammatory mediators, whereas detrimental outcomes associated with high BAC, including neurotoxicity and depressive-like behavior may be due to reduction in neurotropic factors and elevation of inflammatory mediators. Furthermore, new research strategies are suggested.

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Phospholipase A2 is involved in galactosylsphingosine-induced astrocyte toxicity, neuronal damage and demyelination

Cited by 21 publications

References 60 publications

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Inhibition of Piezo1 attenuates demyelination in the central nervous system

The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease

Low Vs. High Alcohol: Central Benefits Vs. Detriments

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