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Cellular and Molecular Neurobiology (2018) 38:1145–1151
https://doi.org/10.1007/s10571-018-0580-y
BRIEF COMMUNICATION
Spasticity Treatment Ameliorates the Ecacy of Melatonin Therapy
in Experimental Autoimmune Encephalomyelitis (EAE) Mouse Model
of Multiple Sclerosis
Majid Ghareghani
1,2
· Kazem Zibara
3
· Hossein Sadeghi
1
· Naser Farhadi
4
Received: 17 November 2017 / Accepted: 20 February 2018 / Published online: 1 March 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease in the central nervous system (CNS). Melatonin
is an effective treatment in MS patients and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.
Melatonin secretion peaks at 2 AM, concomitant with the time at which the muscles are resting and the body is exerting
its antioxidant activity. The current study was designed to investigate combination treatment of baclofen, a muscle relaxant
drug, and melatonin in EAE mice. Results showed that melatonin (Mel) alone or in combination with baclofen (Bac + Mel)
reduced clinical scores and demyelination by significantly increasing myelin oligodendrocyte glycoprotein (MOG) levels,
a marker for mature oligodendrocytes, compared to EAE mice. Moreover, Mel or Bac + Mel therapy caused a significant
increase in IL-4 serum levels, an anti-inflammatory cytokine, whereas IFN-γ serum levels, a pro-inflammatory cytokine,
were significantly reduced. On the other hand, Mel or Bac + Mel caused a significant reduction in malondialdehyde (MDA)
levels, a marker of oxidative stress, in comparison to EAE mice. In contrast, the activity of antioxidant enzymes catalase
(CAT) and superoxide dismutase (SOD) was significantly increased in Mel and Bac + Mel groups. In summary, combination
therapy improved clinical scores and tend to enhance the efficiency of melatonin treatment by further promoting remyeli-
nation, decreasing inflammation, and stimulating the activity of antioxidant enzymes, which suggests that prior spasticity
treatment increases the efficacy of melatonin therapy in EAE mouse model of MS. Further experimental and clinical studies
are needed to ensure the beneficial role of this combination strategy.
Keywords Multiple sclerosis · Melatonin · Spasticity · Baclofen · Muscle relaxant
Introduction
Multiple sclerosis (MS) is a disease of the central nervous
system (CNS) characterized by inflammation and demyeli-
nation in the CNS, with approximately 2.5 million people
suffering from this neurological disorder (Hagemeier et al.,
2012). While the development of MS is not completely
understood, it has been suggested that oxidative stress and
reactive oxygen species (ROS) could be responsible for this
disease since few antioxidants showed efficacy in its treat-
ment (Mirshafiey and Mohsenzadegan 2009). Melatonin, a
natural antioxidant in the CNS, is a free-radical scavenger
which increases the level of antioxidant enzymes, making it
a candidate to treat MS (Reiter et al. 1995; Emamgholipour
et al. 2016). Currently, melatonin is not well studied as a
medication to attenuate the severity of MS (Kang et al. 2001;
Alvarez-Sanchez et al. 2015; Farez et al. 2015; Chen et al.
2016); however, our group showed earlier that melatonin
Majid Ghareghani and Kazem Zibara have contributed equally to
this work.
* Naser Farhadi
naserfarhadi42@yahoo.com; naser.farhadi@yums.ac.ir
1
Medicinal Plants Research Center, Yasuj University
of Medical Sciences, Yasuj, Iran
2
CERVO Brain Research Center, Quebec City, QC G1J 2G3,
Canada
3
ER045, Laboratory of Stem Cells, PRASE, Biology
Department, Faculty of Sciences, Lebanese University,
Beirut, Lebanon
4
Cellular and Molecular Research Center, Yasuj University
of Medical Sciences, Yasuj, Iran
@Phil_Robichaud
@deepthiw
@JoseServera