Intranasal administration of fingolimod (FTY720) attenuates demyelination area in lysolecithin-induced demyelination model of rat optic chiasm

Ghasemi-Kasman, Maryam; Nosratiyan, Nasrin; Hashemian, Mona; Ahmadian, Seyyed-Raheleh; Parsian, Hadi; Mansoor, Sahar

doi:10.1016/j.msard.2022.103518

Cited by 5 publications

(2 citation statements)

References 40 publications

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“…As demyelination is a critical component of EAE and MS ( 6 , 74 ), we wanted to explore in this SD rat model whether MOG would induce spinal cord demyelination detectable by immunohistochemistry, and whether this demyelination would be reversed by TLR2–TLR4 blockade. Fluoromyelin fluorescently stains myelin; hence, a decrease in fluorescence indicates the areas of demyelination ( 65 , 75 ). This is an assessment of the presence of demyelination using fluoromyelin fluorescent intensity of lumbar ventral funiculus from tissue collected from rats in Experiment 2.…”

Section: Resultsmentioning

confidence: 99%

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Kwilasz¹,

Clements²,

Larson³

et al. 2022

Front. Pain Res.

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Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with pain testing. In this study, we characterize a novel low-dose myelin-oligodendrocyte-glycoprotein (MOG)-induced Sprague-Dawley (SD) model of EAE-related pain in male rats, optimized to minimize motor impairments/disabilities. Adult male SD rats were treated with increasing doses of intradermal myelin-oligodendrocyte-glycoprotein (MOG1−125) (0, 4, 8, and 16 μg) in incomplete Freund's adjuvant (IFA) vehicle to induce mild EAE. Von Frey testing and motor assessments were conducted prior to EAE induction and then weekly thereafter to assess EAE-induced pain and motor impairment. Results from these studies demonstrated that doses of 8 and 16 μg MOG1−125 were sufficient to produce stable mechanical allodynia for up to 1 month in the absence of hindpaw motor impairments/disabilities. In the follow-up studies, these doses of MOG1−125, were administered to create allodynia in the absence of confounded motor impairments. Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2–TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days. We found that (+)-NTX also reverses EAE-induced mechanical allodynia in the MOG-induced SD rat model of EAE, supporting parallels between models, but now allowing a protracted timecourse to be examined completely free of motor confounds. Exploring further mechanisms, we demonstrated that both spinal NOD-like receptor protein 3 (NLRP3) and interleukin-17 (IL-17) are necessary for EAE-induced pain, as intrathecal injections of NLRP3 antagonist MCC950 and IL-17 neutralizing antibody both acutely reversed EAE-induced pain. Finally, we show that spinal glial immunoreactivity induced by EAE is reversed by (+)-NTX, and that spinal demyelination correlates with the severity of motor impairments/disabilities. These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2–TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

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Section: Resultsmentioning

confidence: 99%

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Kwilasz¹,

Clements²,

Larson³

et al. 2022

Front. Pain Res.

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“…1% of the total lipid concentration of the mouse hippocampus, and FTY720 caused a 25% increase in the LysoPC concentration from 3.26 to 4.09 nmoles/hippocampus. The increase in LysoPC lipid species in FTY720‐treated animals appears to be somewhat counterintuitive since high concentrations of LysoPC can induce axonal demyelination (Ghasemi‐Kasman et al., 2022; Velasco‐Estevez et al., 2020; Yazdi et al., 2015), and yet FTY720 can inhibit the degeneration of CNS white matter (Sheridan & Dev, 2012). LysoPC levels are also increased following traumatic brain injury (Tzekov et al., 2016) and post‐spinal cord injury (Hanada et al., 2012) and are high in the cerebrospinal fluid (CSF) of MS patients (Pieragostino et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

Magalhães,

Stewart,

Mampay

et al. 2024

Journal of Neurochemistry

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The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system.

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Current non-invasive strategies for brain drug delivery: overcoming blood–brain barrier transport

Zheng,

Yang,

Hou

et al. 2023

Mol Biol Rep

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Intranasal administration of fingolimod (FTY720) attenuates demyelination area in lysolecithin-induced demyelination model of rat optic chiasm

Cited by 5 publications

References 40 publications

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

Current non-invasive strategies for brain drug delivery: overcoming blood–brain barrier transport

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