Teriflunomide's Effect on Glia in Experimental Demyelinating Disease: A Neuroimaging and Histologic Study

Abstract

Teriflunomide altered microglia density and oligodendrocytes differentiation, which was associated with less evident microstructural damage on MRI.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…A reduction in the number of pro-inflammatory M1 Sialoadhesin (SIGLEC-1)-positive or IBA1-positive microglia following TF treatment has been reported in rodent models for various diseases, such as in the brains of mice suffering from neuronal ceroid lipofuscinosis (CLN) [49], in the hippocampus of two different rat models for traumatic brain injury (TBI) [256], in the basal ganglia and the corpus callosum of a Theiler's murine encephalomyelitis virus (TMEV)-induced mouse demyelination model [257], and fewer IBA1-positive cells were also detected in the brains of transient middle cerebral artery occlusion (tMCAO) stroke mice [254]. At high concentrations, TF diminished the LPS-and IFN-γ induced CD68 expression in vitro [258], and following LPS stimulation, the expression of the M2 microglia cytokine IL-10 was slightly increased in rat primary microglia and mixed glial cultures [258].…”

Detection of Monocyte/Macrophage and Microglia Activation in the TMEV Model of Chronic Demyelination Using USPIO‐Enhanced Ultrahigh‐Field Imaging

“…27 Animals were clinically scored by blinded examiners, exhibiting either no apparent abnormality (0), abnormalities in lowered rear (.25), various levels of severity in waddling gait (.5-2.5), impaired righting (3.0-3.5), or moribund (4). 20,21 Animals were evaluated also by rotarod assay. 30 The rotating rod began at 1 rotation of per minute (rpm) and accelerated to 70 rpm with the score quantified as the peak rpm and the animal remains on the rotating rod.…”

“…Induction and maintenance of anesthesia during imaging was achieved by inhalation of 1 L/minute oxygen and isoflurane 4-5% and 1-3%, respectively. 20,21,31 To prevent hypothermia, the core body temperature was continuously monitored with a rectal probe and regulated with an embedded water-heating system. The probe head was maintained at 38°C…”

“…For detecting USPIO+ contrast enhancing lesions (CELs) and assessing brain volumes, T2*-weighted gradient echo MRI brain images were acquired following second-order field-mapbased shimming using a 3D multiecho gradient echo (MEGRE) sequence (2.38 milliseconds 1st echo, 4.4 milliseconds echo spacing, 9 mono-polar echoes, 90 milliseconds repetition time, 18°flip angle, 75% partial-Fourier in reading direction, 27 × 14 × 8 mm field of view, 252 × 180 × 100 matrix, 80 µm isotropic resolution, 50 minutes acquisition time). 20,21 Twenty-four hours prior to in-vivo MRI scanning, USPIO nanoparticles (Molday ION, Cat# CL-30Q02-A2, BioPal Inc, Worcester, MA, USA) were administered via tail vein injection at 15 mg/kg dosage in 10 µL volume. Animals were anesthetized using 5% isofluorane and immobilized for the administration.…”

“…The brain volume segmentation was performed using a previously described multiatlas approach. 20,21 To generate the atlases, regions of interest (ROIs) were outlined manually using 3D Slicer (www.slicer.org) in 10 scans from three different representative animals, 20,21 with the visual aid of Waxholm Atlas v0.6.2. 32 ROIs included the corpus callosum (CC), basal ganglia (BG), thalamus (Th), cortex (Cx), and lateral ventricles (LVs).…”