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

Sanadgol, N. and Golab, F. and Mostafaie, A. and Mehdizadeh, M. and Khalseh, R. and Mahmoudi, M. and Abdollahi, M. and Vakilzadeh, G. and Taghizadeh, G. and Sharifzadeh, M. (2018) 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. Toxicology and Applied Pharmacology, 342. pp. 86-98.

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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. © 2018 Elsevier Inc.

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: beta actin; caspase 3; glial fibrillary acidic protein; immunoglobulin enhancer binding protein; interleukin 1; messenger RNA; myelin; myelin oligodendrocyte glycoprotein; protein Bax; protein bcl 2; triptolide; tumor necrosis factor; diterpene; epoxide; immunoglobulin enhancer binding protein; immunosuppressive agent; neuroprotective agent; phenanthrene derivative; triptolide, animal experiment; animal model; animal tissue; apoptosis; Article; behavior disorder; cell activation; controlled study; demyelination; drug megadose; glia; gliosis; low drug dose; male; motor coordination; motor performance; mouse; multiple sclerosis; nervous system inflammation; nonhuman; oligodendroglia; animal; antagonists and inhibitors; C57BL mouse; disease model; dose response; drug effect; inflammation; metabolism; multiple sclerosis; myelin sheath; pathology; psychomotor disorder, Animals; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Immunosuppressive Agents; Inflammation; Male; Mice; Mice, Inbred C57BL; Motor Skills Disorders; Multiple Sclerosis; Myelin Sheath; Neuroprotective Agents; NF-kappa B; Phenanthrenes
Subjects: WL Nervous System
Depositing User: eprints admin
Date Deposited: 16 Dec 2018 09:51
Last Modified: 17 Aug 2019 04:13
URI: http://eprints.iums.ac.ir/id/eprint/6825

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