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Paeonol Ameliorates Cuprizone-Induced Hippocampal Demyelination and Cognitive Deficits through Inhibition of Oxidative and Inflammatory Events

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Abstract

Multiple sclerosis (MS) is a chronic and inflammatory disorder of the central nervous system with autoimmune nature that is typified by varying degrees of demyelination and axonal damage. Paeonol is an active ingredient in some medicinal plants with anti-inflammatory and neuroprotective property. This study was conducted to reveal whether paeonol can alleviate hippocampal demyelination and cognitive deficits in cuprizone-induced murine model of demyelination as a model of MS. C57BL/6 mice received oral cuprizone (400 mg/kg) for 6 weeks, and paeonol was administered p.o. at two doses of 25 or 100 mg/kg, starting from the second week post-cuprizone for 5 weeks. After assessment of learning and memory in different tasks, oxidative stress and inflammation were evaluated besides immunohistochemical assessment of hippocampal myelin basic protein (MBP). Paeonol (100 mg/kg) properly ameliorated cognitive deficits in Y maze, novel object discrimination (NOD) test, and Barnes maze with no significant improvement of performance in passive avoidance task. In addition, paeonol treatment at the higher dose was also associated with partial restoration of hippocampal level of oxidative stress and inflammatory markers including MDA, ROS, GSH, SOD, catalase, NF-kB, and TNF. Besides, paeonol improved MMP as an index of mitochondrial integrity and health and reduced MPO as a factor of neutrophil infiltration. Furthermore, paeonol treatment prevented hippocampal MBP immunoreactivity, indicating its prevention of demyelination. In conclusion, the current study showed the preventive effect of paeonol against cuprizone-induced demyelination and cognitive deficits through reversing most oxidative stress- and inflammation-related parameters in addition to its improvement of mitochondrial health.

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Availability of Data and Materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

GSH:

Glutathione (reduced form)

IL-1β:

Interleukin 1β

MBP:

Myelin basic protein

MDA:

Malondialdehyde

MMP:

Mitochondrial membrane potential

MPO:

Myeloperoxidase

MS:

Multiple sclerosis

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NOD:

Novel object discrimination

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TLR4:

Toll-like receptor 4

TNFα:

Tumor necrosis factor α

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Funding

This research study was the results of Ph.D. student thesis project that was approved by Faculty of Basic Sciences (Shahed University, Tehran, Iran) in 2020. Shahed University,1399.041,Mehrdad Roghani

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Authors and Affiliations

  1. Department of Biology, Faculty of Basic Sciences, Shahed University, Tehran, Iran

    Soosan Pourmohammadi

  2. Neurophysiology Research Center, Shahed University, Tehran, Iran

    Mehrdad Roghani, Zahra Kiasalari & Mohsen Khalili

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  1. Soosan Pourmohammadi
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  2. Mehrdad Roghani
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  3. Zahra Kiasalari
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  4. Mohsen Khalili
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Contributions

S.P. conducted the experiments and helped in the data analysis and manuscript preparation. Z.K. and M.R. designed the study, supervised conductance of the experiments, and prepared the manuscript. M.R. performed statistical analysis of data and M.Kh. helped in designing the experiments and preparation of the manuscript.

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Correspondence to Mehrdad Roghani.

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All experimental procedures of this study were conducted under ethical committee supervision of Shahed University (Tehran, Iran) that was in accordance to NIH guidelines for the care and use of laboratory animals. All efforts were made to minimize number of animals and to lower their sufferings. The present study was approved by Institutional Ethics Committee of the Shahed University (Approval ID: IR.SHAHED.REC.1399.041).

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Pourmohammadi, S., Roghani, M., Kiasalari, Z. et al. Paeonol Ameliorates Cuprizone-Induced Hippocampal Demyelination and Cognitive Deficits through Inhibition of Oxidative and Inflammatory Events. J Mol Neurosci 72, 748–758 (2022). https://doi.org/10.1007/s12031-021-01951-2

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