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The Effect of Melatonin on Behavioral, Molecular, and Histopathological Changes in Cuprizone Model of Demyelination

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Abstract

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The protective effects of melatonin (MLT) on various neurodegenerative diseases, including MS, have been suggested. In the present study, we examined the effect of MLT on demyelination, apoptosis, inflammation, and behavioral dysfunctions in the cuprizone toxic model of demyelination. C57BL/6J mice were fed a chaw containing 0.2 % cuprizone for 5 weeks and received two doses of MLT (50 and 100 mg/kg) intraperitoneally for the last 7 days of cuprizone diet. Administration of MLT improved motor behavior deficits induced by cuprizone diet. MLT dose-dependently decreased the mean number of apoptotic cells via decreasing caspase-3 and Bax as well as increasing Bcl-2 levels. In addition, MLT significantly enhanced nuclear factor-κB activation and decreased heme oxygenase-1 level. However, MLT had no effect on interleukin-6 and myelin protein production. Our data revealed that MLT improved neurological deficits and enhanced cell survival but was not able to initiate myelin production in the cuprizone model of demyelination. These findings may be important for the design of potential MLT therapy in demyelinating disorders, such as MS.

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Abbreviations

MLT:

Melatonin

CNS:

Central nervous system

ECL:

Electrochemiluminescence

EAE:

Experimental autoimmune encephalomyelitis

H&E:

Hematoxylin and eosin

HO:

Heme oxygenase

IL-6:

Interleukin-6

LFB:

Luxol Fast Blue

MS:

Multiple sclerosis

NFκB:

Nuclear factor-κB

PFA:

Paraformaldehyde

BBB:

Blood brain barrier

PNS:

Peripheral nervous system

PLP:

Proteolipid protein

PMP-22:

Peripheral myelin protein 22

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

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Acknowledgments

This study was supported by the Shefa Neuroscience Research Center grant related to Dr-Thesis 26222, Tehran University of Medical Sciences, and Iran National Science Foundation (INSF).

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Authors and Affiliations

  1. Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran

    Gelareh Vakilzadeh, Tahereh Ghadiri & Ali Gorji

  2. Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Gelareh Vakilzadeh, Tahereh Ghadiri & Mohammad Sharifzadeh

  3. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fariba Khodagholi

  4. Infectious Diseases Research Center, Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Amir Ghaemi

  5. Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Farshid Noorbakhsh

  6. Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran

    Mohammad Sharifzadeh

  7. Department of Neurology, Klinik und Poliklinik für Neurochirurgie, Epilepsy Research Center, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Ali Gorji

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  1. Gelareh Vakilzadeh
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  2. Fariba Khodagholi
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Correspondence to Mohammad Sharifzadeh or Ali Gorji.

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Vakilzadeh, G., Khodagholi, F., Ghadiri, T. et al. The Effect of Melatonin on Behavioral, Molecular, and Histopathological Changes in Cuprizone Model of Demyelination. Mol Neurobiol 53, 4675–4684 (2016). https://doi.org/10.1007/s12035-015-9404-y

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