Mechanisms of lysophosphatidylcholine‐induced demyelination: A primary lipid disrupting myelinopathy

Plemel, Jason R.; Michaels, Nathan J.; Weishaupt, Nina; Caprariello, Andrew V.; Keough, Michael B.; Rogers, James A.; Yukseloglu, Aran; Lim, Jae-Hyun; Patel, Vikas; Rawji, Khalil S.; Jensen, Samuel K.; Teo, Wulin; Heyne, Belinda; Whitehead, Shawn N.; Stys, Peter K.

doi:10.1002/glia.23245

Cited by 154 publications

(137 citation statements)

References 112 publications

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“…To further investigate the potential therapeutic properties of GsMTx4, we employed an in vivo model of toxin‐induced focal demyelination of cortical brain tissue (Irvine & Blakemore, ; Plemel et al, ). In this case, we used the toxin LPC (Plemel et al, ) to determine both the protective effects of GsMTx4 in vivo and to investigate if these effects were specific to psychosine. In this set of experiments, mice were injected in the left and right cerebral hemispheres (Figure a,b) with either: PBS, LPC (0.1%), or LPC + GsMTx4 (3 μM) (Figure c–e).…”

Section: Resultsmentioning

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: Resultsmentioning

confidence: 99%

“…Lysophosphatidylcholine (LPC; Sigma, #L4129) is an endogenous lysophospholipid that disrupts myelin-associated lipids (Plemel et al, 2018) leading to focal demyelination. It has been shown that the LPCinduced demyelination of axons requires an increase in intracellular Ca 2+ levels (Fu, Wang, Huff, Shi, & Cheng, 2007).…”

Section: Reagentsmentioning

confidence: 99%

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Velasco‐Estevez

Gadalla

Liñan-Barba

et al. 2019

Glia

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“…LPC is a detergent-like membrane solubilizing agent that disrupts myelin lipids (29). Plemel et al (62) reported that LPC integrated into cellular membranes and rapidly induced cell membrane permeability, nonspecifically disrupting myelin lipids in mice. Now, we have shown that demyelination of the ACC impaired PA learning and memory retrieval (Fig.…”

Section: Discussionmentioning

confidence: 99%

Schema‐like learning and memory consolidation acting through myelination

et al. 2019

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Memory is a dynamic brain function that is continually processed after encoding. Although psychologic concepts of mental schema are now well established, they have rarely been considered in animal studies. We used a behavior paradigm of multiple flavor-place paired associates (PAs) and showed that memory schema facilitates fast acquisition of new PAs in a single trial. The hippocampus is necessary for the encoding of new PAs and for memory retrieval within a certain time window—24 h following new PA consolidation. Whereas the anterior cingulate cortex (ACC) plays a critical role for dynamic PA learning and consolidation during training sessions, ACC is essential in schema representation and activation. New myelin generation is essential for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. Here, we show that newly formed OL progenitor cells and mature OLs are increased following repeated PA learning and that establishment of the memory schema is associated with enhanced myelin strength in the ACC region. Furthermore, to ensure that myelination is necessary for the acquisition of paired-associate learning, ACC lysolecithin-induced demyelination revealed impaired PA learning associated with decrease in ACC θ band power and reduced spike-field coherence and phase-locking in ACC.—Hasan, M., Kanna, M. S., Jun, W., Ramkrishnan, A. S., Iqbal, Z., Lee, Y., Li, Y. Schema-like learning and memory consolidation acting through myelination.

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“…LPC is a component of oxidized low-density lipoproteins and due to its ability to selectively target myelin, it is used to induce focal demyelination. The mechanism of action of this gliotoxin was only recently uncovered (Plemel et al, 2018). LPC was successfully used for the induction of focal demyelination in the ON of rats when applied 2 mm posterior to the globe or at the optic chiasm (Mozafari et al, 2011;You et al, 2015;You, Klistorner, Thie, & Graham, 2011).…”

Section: Ont Rodent Modelsmentioning

confidence: 99%

Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

Bastakis

Ktena

Καραγωγεωσ

et al. 2019

Developmental Neurobiology

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Pathologies of the optic nerve could result as primary insults in the visual tract or as secondary deficits due to inflammation, demyelination, or compressing effects of the surrounding tissue. The extent of damage may vary from mild to severe, differently affecting patient vision, with the most severe forms leading to complete uni‐ or bilateral visual loss. The aim of researchers and clinicians in the field is to alleviate the symptoms of these, yet uncurable pathologies, taking advantage of known and novel potential therapeutic approaches, alone or in combinations, and applying them in a limited time window after the insult. In this review, we discuss the epidemiological and clinical profile as well as the pathophysiological mechanisms of two main categories of optic nerve pathologies, namely traumatic optic neuropathy and optic neuritis, focusing on the demyelinating form of the latter. Moreover, we report on the main rodent models mimicking these pathologies or some of their clinical aspects. The current treatment options will also be reviewed and novel approaches will be discussed.

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Mechanisms of lysophosphatidylcholine‐induced demyelination: A primary lipid disrupting myelinopathy

Cited by 154 publications

References 112 publications

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Schema‐like learning and memory consolidation acting through myelination

Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

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