The effects of a combination of ion channel inhibitors on pathology in a model of demyelinating disease

Gopalasingam, Gopana; Bartlett, Carole A.; McGonigle, Terence; Majimbi, Maimuna; Warnock, Andrew; Ford, Abbey; Gough, Alexander; Toomey, Lillian M.; Fitzgerald, Maria

doi:10.1016/j.msard.2019.06.005

Cited by 6 publications

(3 citation statements)

References 62 publications

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“…It is known that by 1 week of cuprizone administration, microglia are activated in the corpus callosum 23 , with astrocytes showing morphological changes as early as 1 week and increasing in density by 3 weeks 24 . In the current study, similar inflammatory changes were accompanied by increased immunoreactivity of oxidative stress markers for protein nitration and DNA damage, which we have previously demonstrated following 3 weeks of cuprizone administration 57 . The higher protein nitration in rostral corpus callosum with powdered cuprizone compared to the caudal region is an interesting finding that warrants further mechanistic investigations.…”

Section: Discussionsupporting

confidence: 88%

Cuprizone feed formulation influences the extent of demyelinating disease pathology

Toomey

Papini

Lins

et al. 2021

Sci Rep

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Cuprizone is a copper-chelating agent that induces pathology similar to that within some multiple sclerosis (MS) lesions. The reliability and reproducibility of cuprizone for inducing demyelinating disease pathology depends on the animals ingesting consistent doses of cuprizone. Cuprizone-containing pelleted feed is a convenient way of delivering cuprizone, but the efficacy of these pellets at inducing demyelination has been questioned. This study compared the degree of demyelinating disease pathology between mice fed cuprizone delivered in pellets to mice fed a powdered cuprizone formulation at an early 3 week demyelinating timepoint. Within rostral corpus callosum, cuprizone pellets were more effective than cuprizone powder at increasing astrogliosis, microglial activation, DNA damage, and decreasing the density of mature oligodendrocytes. However, cuprizone powder demonstrated greater protein nitration relative to controls. Furthermore, mice fed control powder had significantly fewer mature oligodendrocytes than those fed control pellets. In caudal corpus callosum, cuprizone pellets performed better than cuprizone powder relative to controls at increasing astrogliosis, microglial activation, protein nitration, DNA damage, tissue swelling, and reducing the density of mature oligodendrocytes. Importantly, only cuprizone pellets induced detectable demyelination compared to controls. The two feeds had similar effects on oligodendrocyte precursor cell (OPC) dynamics. Taken together, these data suggest that demyelinating disease pathology is modelled more effectively with cuprizone pellets than powder at 3 weeks. Combined with the added convenience, cuprizone pellets are a suitable choice for inducing early demyelinating disease pathology.

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Section: Discussionsupporting

confidence: 88%

Cuprizone feed formulation influences the extent of demyelinating disease pathology

Toomey

Papini

Lins

et al. 2021

Sci Rep

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“…New therapies to enhance remyelination offer directions for new treatments for patients with demyelinating injury, including hypoxia, white matter injury, multiple sclerosis, TBI, and also developmental disorders such as autism and schizophrenia. Recent experiments have shown that ion channel inhibitors can rescue some of the defects found in the demyelinating model of cuprizone treatment ( Gopalasingam et al, 2019 ) and partial optic nerve transection ( O’Hare Doig et al, 2017 ). Specifically, a cocktail of ion channel inhibitors to block calcium entry partially rescued OPC loss and decreased the number of atypical nodes of Ranvier, although paranode length decreases were not rescued, indicating that excessive calcium is an important contributor of demyelinating injury.…”

Section: Disease and Treatmentmentioning

confidence: 99%

Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics

2022

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The development of neuronal circuitry required for cognition, complex motor behaviors, and sensory integration requires myelination. The role of glial cells such as astrocytes and microglia in shaping synapses and circuits have been covered in other reviews in this journal and elsewhere. This review summarizes the role of another glial cell type, oligodendrocytes, in shaping synapse formation, neuronal circuit development, and myelination in both normal development and in demyelinating disease. Oligodendrocytes ensheath and insulate neuronal axons with myelin, and this facilitates fast conduction of electrical nerve impulses via saltatory conduction. Oligodendrocytes also proliferate during postnatal development, and defects in their maturation have been linked to abnormal myelination. Myelination also regulates the timing of activity in neural circuits and is important for maintaining the health of axons and providing nutritional support. Recent studies have shown that dysfunction in oligodendrocyte development and in myelination can contribute to defects in neuronal synapse formation and circuit development. We discuss glutamatergic and GABAergic receptors and voltage gated ion channel expression and function in oligodendrocyte development and myelination. We explain the role of excitatory and inhibitory neurotransmission on oligodendrocyte proliferation, migration, differentiation, and myelination. We then focus on how our understanding of the synaptic connectivity between neurons and OPCs can inform future therapeutics in demyelinating disease, and discuss gaps in the literature that would inform new therapies for remyelination.

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“…Several evidences support the notion that aberrant Cav-mediated currents contribute to the pathophysiology of MS or EAE. Increased Ca 2+ influx through Cav was assumed to facilitate neurological impairment and histological damage in EAE mice and, by inference, MS [ 146 ]. Pregabalin (Lyrica ® ) is prescribed to MS patients to treat neuropathic pain by targeting Cav [ 62 ] and, in addition, it could provide neuroprotection by inhibiting exaggerated Cav currents during excitotoxicity and neuroinflammation.…”

Section: Voltage-gated Channels In Oligodendroglial Cells and Myelinationmentioning

confidence: 99%

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

Cherchi

Bulli

Venturini

et al. 2021

IJMS

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Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation. Moreover, OPCs are crucial players in neuro-glial communication as they receive synaptic inputs from neurons and express ion channels and neurotransmitter/neuromodulator receptors that control their maturation. Ion channels are recognized as attractive therapeutic targets, and indeed ligand-gated and voltage-gated channels can both be found among the top five pharmaceutical target groups of FDA-approved agents. Their modulation ameliorates some of the symptoms of MS and improves the outcome of related animal models. However, the exact mechanism of action of ion-channel targeting compounds is often still unclear due to the wide expression of these channels on neurons, glia, and infiltrating immune cells. The present review summarizes recent findings in the field to get further insights into physio-pathophysiological processes and possible therapeutic mechanisms of drug actions.

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The effects of a combination of ion channel inhibitors on pathology in a model of demyelinating disease

Cited by 6 publications

References 62 publications

Cuprizone feed formulation influences the extent of demyelinating disease pathology

Cuprizone feed formulation influences the extent of demyelinating disease pathology

Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

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