In vivo mapping of rat brain partial white matter content using hexachlorophene-induced neurotoxicity model.

Segmentation of the white matter in MRI scans of the rat brain presents a significant challenge due to the low contrast. Existing anatomical reference maps of rat brain are usually constructed from fixed tissue, which may suffer from geometrical distortions due to fixation/processing. To significantly increase the in vivo contrast between white and gray matter in the rat brain we used a known neurotoxicant hexachlorophene, which produces selective white matter damage.

Performance of the prospective T MRI biomarker of neurotoxicity in a trimethyltin model in rats at 7 T.

The assessment of the sensitivity and specificity of any potential biomarker against the gold standard is an important step in the process of its qualification by regulatory authorities. Such qualification is an important step towards incorporating the biomarker into the panel of tools available for drug development. In the current study we analyzed the sensitivity and specificity of T MRI relaxometry to detect trimethyltin-induced neurotoxicity in rats.

The effects of long-term methylphenidate administration and withdrawal on progressive ratio responding and T MRI in the male rhesus monkey.

Methylphenidate is a frequently prescribed drug treatment for Attention-Deficit/Hyperactivity Disorder. However, methylphenidate has a mode of action similar to amphetamine and cocaine, both powerful drugs of abuse. There is lingering concern over the long-term safety of methylphenidate, especially in a pediatric population, where the drug may be used for years.

Optimization of Detection of Gadodiamide Brain Retention in Rats Using Quantitative T Mapping and Intraperitoneal Administration.

Background: Currently, the gadolinium retention in the brain after the use of contrast agents is studied by T -weighted magnetic resonance imaging (MRI) (T w) and T mapping. The former does not provide easily quantifiable data and the latter requires prolonged scanning and is sensitive to motion. T mapping may provide an alternative approach.

Global Neurotoxicity: Quantitative Analysis of Rat Brain Toxicity Following Exposure to Trimethyltin.

The organotin, trimethyltin (TMT), is a highly toxic compound. In this study, silver-stained rat brain sections were qualitatively and quantitatively evaluated for degeneration after systemic treatment with TMT. Degenerated neurons were counted using image analysis methods available in the HALO image analysis software.

Quantitative Neurotoxicology: An Assessment of the Neurotoxic Profile of Kainic Acid in Sprague Dawley Rats.

This study consisted of a qualitative and quantitative assessment of neuropathological changes in kainic acid (KA)-treated adult male rats. Rats were administered a single 10 mg/kg intraperitoneal injection of KA or the same volume of saline and sacrificed 24 or 48 hours posttreatment. Brains were collected, sectioned coronally (∼ 81 slices), and stained with amino cupric silver to reveal degenerative changes.

Sex differences in the effect of acute administration of nicotine on MRS-measured metabolic profile of the rat brain.

Women are less able to stop smoking than men. Elucidation of sex differences in the tobacco addiction could facilitate personalized treatment. Specialized brain reward systems are controlling the behavior through reinforcement using specific neuromediators.

A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.

Unlabelled: Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats.

Comparison of quantitative T and ADC mapping in the assessment of 3-nitropropionic acid-induced neurotoxicity in rats.

To assess the relative performance of MRI T relaxation and ADC mapping as potential biomarkers of neurotoxicity, a model of 3-nitropropionic acid (NP)-induced neurodegeneration in rats was employed. Male Sprague-Dawley rats received NP (N = 20, 16-20 mg/kg, ip or sc) or saline (N = 6, 2 ml/kg, ip) daily for 3 days. MRI was performed using a 7 T system employing quantitative T and ADC mapping based on spin echo pulse sequence.

Changes in the metabolome and microRNA levels in biological fluids might represent biomarkers of neurotoxicity: A trimethyltin study.

Neurotoxicity has been linked with exposure to a number of common drugs and chemicals, yet efficient, accurate, and minimally invasive methods to detect it are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid have great potential due to the relative ease of sampling but at present, data on their expression and translation are lacking or inconsistent. In this pilot study using a trimethyl tin rat model of central nervous system toxicity, we have applied state-of-the-art assessment techniques to identify potential individual biomarkers and patterns of biomarkers in serum, plasma, urine or cerebral spinal fluid that may be indicative of nerve cell damage and degeneration.

The Pathophysiological Sequence of Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Male Mice.

In search of the sequence of pathogenic events leading to glucocorticoid-induced osteonecrosis, we determined the molecular, biomechanical, cellular, and vascular changes in the femur of C57BL/6 mice receiving prednisolone for 14, 28, or 42 days. The femoral head, but not the distal femur, of mice treated for 14 days showed a decrease in the expression of the hypoxia-inducible factor (Hif)-1α and vascular endothelial growth factor (VEGF), the number of osteoblasts, and bone formation rate and strength and showed an increase in osteoclasts. These changes were accompanied by conversion of the normal dendritic vasculature to pools of edema as detected by magnetic resonance imaging, providing robust diagnostic evidence of early osteonecrosis.

High resolution imaging of the mitral valve in the natural state with 7 Tesla MRI.

Imaging techniques of the mitral valve have improved tremendously during the last decade, but challenges persist. The delicate changes in annulus shape and papillary muscle position throughout the cardiac cycle have significant impact on the stress distribution in the leaflets and chords, thus preservation of anatomically accurate positioning is critical. The aim of this study was to develop an in vitro method and apparatus for obtaining high-resolution 3D MRI images of porcine mitral valves in both the diastolic and systolic configurations with physiologically appropriate annular shape, papillary muscle positions and orientations, specific to the heart from which the valve was harvested.

Brain endothelial dysfunction following pyrithiamine induced thiamine deficiency in the rat.

Prolonged vitamin B (thiamine) deficiency can lead to neurological disorders such as Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome (WKS) in humans. These thiamine deficiency disorders have been attributed to vascular leakage, blood-brain barrier breakdown and neuronal loss in the diencephalon and brain stem. However, endothelial dysfunction following thiamine deficiency and its relationship to the phenomenon of neurodegeneration has not been clearly elucidated.

Magnetic resonance spectroscopic analysis of neurometabolite changes in the developing rat brain at 7T.

We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippocampus and anterior cingulate cortex of the developing rat brain from postnatal days 14-70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e.

Longitudinal diffusion tensor imaging of the rat brain after hexachlorophene exposure.

Longitudinal MRI employing diffusion tensor imaging and T mapping approaches has been applied to investigate the mechanisms of white matter damage caused by acute hexachlorophene neurotoxicity in rats in vivo. Male Sprague-Dawley rats were administered hexachlorophene orally once a day for five consecutive days at a dose of 30mg/kg and were monitored in 7T MRI scanner at days 0 (baseline), 3, 6, 13, and 20 following the first hexachlorophene dose. Quantitative T maps as well as a number of diffusion tensor parameters (fractional anisotropy, radial and axial diffusivity, apparent diffusion coefficient, and trace) were calculated from corresponding MR images.

Quantification and reproducibility assessment of the regional brain T relaxation in naïve rats at 7T.

Purpose: To measure the reproducibility of T relaxation and to determine the statistical power of T mapping in the rat brain as a characteristic of the baseline performance of the T relaxation as a potential biomarker of neurotoxicity.

Materials And Methods: Multislice multiecho spin-echo imaging was utilized to obtain the quantitative T maps in 138 naïve rats at 7T. Images were skull-stripped and coregistered to the common anatomical reference.

Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward.

Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues.

Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage.

Various iron-oxide nanoparticles have been in use for a long time as therapeutic and imaging agents and for supplemental delivery in cases of iron-deficiency. While all of these products have a specified size range of ∼ 40 nm and above, efforts are underway to produce smaller particles, down to ∼ 1 nm. Here, we show that after a 24-h exposure of SHSY-5Y human neuroblastoma cells to 10 μg/ml of 10 and 30 nm ferric oxide nanoparticles (Fe-NPs), cellular dopamine content was depleted by 68 and 52 %, respectively.

Quantitative Assessment of MRI T2 Response to Kainic Acid Neurotoxicity in Rats in vivo.

The aim of this study was to assess quantitative changes in T2 relaxation using magnetic resonance imaging approaches in rats exposed to kainic acid to assess the utility of such endpoints as biomarkers of neurotoxicity. Quantitative T2 mapping was performed in 21 rats before and 2, 24, and 48 h after a single ip injection of 10 mg/kg of kainic acid. Three methods of quantifying T2 changes were explored: (1) Thresholding: all voxels exhibiting T2 ≤ 72 ms were designated normal tissue, whereas voxels exhibiting T2 > 72 ms were designated as lesioned tissue; (2) Statistical mapping: T2 maps obtained after treatment were statistically compared with averaged "baseline" maps, voxel-by-voxel; (3) Within-subject difference from baseline: for each individual the baseline T2 map was subtracted from the T2 map obtained after treatment.

The use of MRI to assist the section selections for classical pathology assessment of neurotoxicity.

MRI was utilized to probe T2 changes in living brain following exposure of rats to one of ten classical neurotoxicants. Brains were subsequently perfused for classical neuropathology examination. This approach was predicated on the assumption that the T2 changes represent loci of neurotoxicity encompassing those seen using neuropathology techniques.

In vivo MRI assessment of knee cartilage in the medial meniscal tear model of osteoarthritis in rats.

We present a new approach for quantifying the degradation of knee cartilage in the medial meniscal tear (MMT) model of osteoarthritis in the rat. A statistical strategy was used to guide the selection of a region of interest (ROI) from the images obtained from a pilot study. We hypothesize that this strategy can be used to localize a region of cartilage most vulnerable to MMT-induced damage.

Faster recovery of cerebral perfusion in SOD1-overexpressed rats after cardiac arrest and resuscitation.

Background And Purpose: Protracted hypoperfusion is one of the hallmarks of secondary cerebral derangement after cardiac arrest and resuscitation (CAR), and reactive oxygen species have been implicated in reperfusion abnormalities.

Methods: Using transgenic (Tg) rats overexpressing copper zinc superoxide dismutase (SOD1), we investigated the role of this intrinsic antioxidant in the restoration of cerebral blood flow (CBF) after CAR. Nine Tg and 11 wild-type (WT) rats were subjected to a nominal 15-minute cardiac arrest, and CBF was measured using the noninvasive arterial spin labeling MRI method before and during cardiac arrest, and 0 to 2 hours and 1 to 5 days after resuscitation.

The T- and L-type calcium channel blocker (CCB) mibefradil attenuates leg edema induced by the L-type CCB nifedipine in the spontaneously hypertensive rat: a novel differentiating assay.

Among the L-type calcium channel blockers (CCBs), particularly dihydropyridines like nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester], a common adverse effect is vasodilatory edema. Newer CCBs, such as the T- and L-type CCB, mibefradil [(1S,2S)-2-[2[[3-(2-benzimidazolylpropyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride hydrate], demonstrate antihypertensive efficacy similar to that of their predecessors but seem to have a reduced propensity to cause edema. Using a magnetic resonance imaging (MRI) T(2) mapping technique, we investigated the ability of mibefradil to reduce extracellular water accumulation caused by the L-type CCB, nifedipine, in the hindleg skeletal muscle of the spontaneously hypertensive rat.

Deferoxamine improves early postresuscitation reperfusion after prolonged cardiac arrest in rats.

The no-reflow phenomenon and delayed hypoperfusion after transient cardiac arrest (CA) impede postischemic recovery. Activation of lipid peroxidation (LPO) after ischemia and reperfusion is considered one of the mechanisms responsible for such abnormalities. The present study investigates the influence of iron-dependent LPO inhibitor deferoxamine (DFO) on the cerebral perfusion after prolonged CA and resuscitation.