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Toxicol Appl Pharmacol. 2018 Mar 1;342:86-98. doi: 10.1016/j.taap.2018.01.023. Epub 2018 Jan 31.

Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair.

Author information

1
Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
2
Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran.
3
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
4
Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran; Faculty of Advanced Technologies in Medicine, Department of Anatomical Sciences, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
5
Department of Chemical Engineering, Babol Noshirvani University of Technology, Babol, Iran.
6
Department of Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA, USA.
7
Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
8
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
9
Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran; Rehabilitation Research Center, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran.
10
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: msharifzadeh@sina.tums.ac.ir.

Abstract

Cuprizone (Cup) is a copper chelating agent frequently used to study factors that affect oligodendrocytes (OLGs) death and acute demyelination. Triptolide (TP), a nuclear factor-kappaB (NF-κB) blocker, is a major bioactive component of Tripterygium wilfordii Hook f. (TWHf) with various therapeutic activities. In this study, we examined the effects of TP on neuroglia activation, inflammation, apoptosis, demyelination, and behavioral deficits in the Cup-induced toxic model of multiple sclerosis (MS). C57BL/6 J mice were fed with chow containing 0.2% Cup for 6 weeks to induce detectable neuroinflammation and myelin loss. TP was administered intraperitoneally at different doses (125, 250 or 500 μg/kg/day) during the last week of the Cup challenge. Although TP substantially decreased Cup-induced NF-κB extra activation, TNF-α and IL-1 over expression, and gliosis in a dose-dependent manner, only low dose of TP (TP-125) was able to raise the number of OLGs precursor cells (NG-2+/O4+), reduce Bax/Bcl-2 ratio and improve behavioral deficits. In addition, TP-125 decreased NF-κB activation on GFAP+ astrocytes more than MAC-3+ microglial and MOG+ oligodendrocytes which suggested the possibility of specific dampening of NF-κB signaling in reactive astrocytes. Behavioral assessments by open-field and rota-rod tests showed that only TP-125 notably improved motor function and motor coordination compared to the Cup group. These findings highlight the pivotal role of NF-κB signaling in the oligodendrogenesis and lesion reduction in demyelination diseases such as MS.

KEYWORDS:

Apoptosis; Cuprizone; Demyelination; Multiple sclerosis; Neuroinflammation; Triptolide

PMID:
29407366
DOI:
10.1016/j.taap.2018.01.023
[Indexed for MEDLINE]

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