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 Publisher Pubmed



Sanadgol N^{1, 2} ; Golab F³ ; Mostafaie A⁴ ; Mehdizadeh M^{3, 5} ; Khalseh R⁶ ; Mahmoudi M^{7, 11} ; Abdollahi M⁸ ; Vakilzadeh G² ; Taghizadeh G^{9, 10} ; Sharifzadeh M² Show Affiliations
Source: Toxicology and Applied Pharmacology Published:2018

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.