Trifluoperazine reduces cuprizone-induced demyelination via targeting Nrf2 and IKB in mice

Khaledi, Ehsan; Noori, Tayebeh; Mohammadi-Farani, Ahmad; Sureda, Antoni; Dehpour, Ahmad Reza; Yousefi‐Manesh, Hasan; Sobarzo‐Sánchez, Eduardo; Shirooie, Samira

doi:10.1016/j.ejphar.2021.174432

Cited by 13 publications

(8 citation statements)

References 73 publications

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“…Various neuronal centers, such as the association cortex, sensorimotor cortex, subcortical nuclei, cerebellum, or brainstem, intensively communicate to orchestrate the movement of multiple body parts as required to accomplish intended actions, such as walking. There are numerous testing paradigms available to study motor behavior in mice and rats, including the pole test [ 53 , 54 , 55 ], the beam walking test [ 53 , 56 , 57 ], the wire hang test [ 58 , 59 ], the cylinder test, the open field test, different running wheels, different swimming test paradigms, the rotarod test, or footprint analyses [ 60 ]. These tests have pros and cons, and it is essential to note that there are very few purely motor behavioral tasks.…”

Section: General Aspects Of the Assessment Of Motor Behavior In Rodentsmentioning

confidence: 99%

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

Lubrich

Giesler

Kipp

2022

IJMS

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Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system’s white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.

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Section: General Aspects Of the Assessment Of Motor Behavior In Rodentsmentioning

confidence: 99%

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

Lubrich

Giesler

Kipp

2022

IJMS

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“…IKB-α is a protein responsible for NFκB sequestration in the cytoplasm, where it is unable to perform its transcriptional functions (Liu et al, 2017 ). In cuprizone studies, drugs found to increase IκB levels were protective (Khaledi et al, 2021 ), while in developmental studies of the inflammatory molecule S100B, delays in maturation of OPCs were observed concordant to NFκB activation, albeit through the RAGE pathway (Santos et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

Rouillard

Sutter

et al. 2022

Front. Cell. Neurosci.

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HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP). We have recently determined that progenitor cells from multiple sclerosis patients exhibit a cellular senescent phenotype and release extracellular HMGB1 which directly impaired the maturation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes (OLs). Herein, we report that administration of recombinant HMGB1 into the spinal cord at the time of lysolecithin administration resulted in arrest of OPC differentiation in vivo, and a profound impairment of remyelination. To define the receptor by which extracellular HMGB1 mediates its inhibitory influence on OPCs to impair OL differentiation, we tested selective inhibitors against the four primary receptors known to mediate the effects of HMGB1, the toll-like receptors (TLRs)-2, -4, -9 or the receptor for advanced glycation end-products (RAGE). We found that inhibition of neither TLR9 nor RAGE increased OL differentiation in the presence of HMGB1, while inhibition of TLR4 resulted in partial restoration of OL differentiation and inhibiting TLR2 fully restored differentiation of OLs in the presence of HMGB1. Analysis of transcriptomic data (RNAseq) from OPCs identified an overrepresentation of NFκB regulated genes in OPCs when in the presence of HMGB1. We found that application of HMGB1 to OPCs in culture resulted in a rapid and concentration dependent shift in NFκB nuclear translocation which was also attenuated with coincident TLR2 inhibition. These data provide new information on how extracellular HMGB1 directly affects the differentiation potential of OPCs. Recent and past evidence for elevated HMGB1 released from senescent progenitor cells within demyelinated lesions in the MS brain suggests that a greater understanding of how this molecule acts on OPCs may unfetter the endogenous remyelination potential in MS.

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“…[ 48 ] When administered in mice, TF reduced oxidative stress and neuroinflammation induced by cuprizone (a copper‐chelating agent involved in multiple sclerosis lesions) by promoting antioxidant enzymes expression via Nrf2 activation. [ 78 ] Moreover, TF also improved movement disorders, making it a potential adjuvant therapy, for example, in multiple sclerosis. [ 78 ]…”

Section: Ptz As Nrf2/are Pathway Modulatorsmentioning

confidence: 99%

“…[ 78 ] Moreover, TF also improved movement disorders, making it a potential adjuvant therapy, for example, in multiple sclerosis. [ 78 ]…”

Section: Ptz As Nrf2/are Pathway Modulatorsmentioning

confidence: 99%

Phenothiazines: Nrf2 activation and antioxidant effects

Egbujor,

Tucci,

Buttari

et al. 2024

J Biochem & Molecular Tox

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Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch‐like ECH‐associated protein 1/nuclear factor erythroid 2‐related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of “off‐target” effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non‐electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non‐electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress‐mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas.

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Trifluoperazine reduces cuprizone-induced demyelination via targeting Nrf2 and IKB in mice

Cited by 13 publications

References 73 publications

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

Phenothiazines: Nrf2 activation and antioxidant effects

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