Quantitative Assessment of Trimethyltin, Kainic Acid and Pyrithiamine Neurotoxicity in Rat Brain and its Correlation with MR Imaging

Abstract

Toxicagents such as trimethlytin (TMT), kainic acid (KA) and pyrithiamine (PT) induce neurotoxicity. Previous studies have reported degeneration in cortex, hippocampus, olfactory bulb, thalamus a swell as various other brain areas following exposure. Quantitative assessment of the extent of the degeneration is essential for understanding the functional changes due to such toxicity. In the current study, quantitative analyses of the pathological changes associated with single i.p. injections of TMT(12 mg/kg), KA (10 mg/kg) and PT (.25 mg/kg) were performed using tissue classification and area quantification algorithms based on stain color and OD available in HALO™ image analysis software. Sections containing brain areas to be compared to MRI images were chosen from 81 coronal sections of the whole rat brain stained with amino‐cupric silver and subsequently digitalized. Rats treated with TMT showed degeneration in amygdaloid nucleus (11.79%), cortex (7.71%), hippocampus(6.28%), hypothalamus (5.81%), septal region(4.92%), olfactory bulb (4.72%), thalamus (2.82%), nucleus accumbens (2.34%), caudateputamen (2.11%) and substantia nigra (0.40%). Cortical and hippocampaldegeneration in KA treated animals were 5.78% and 4.47%, respectively. Thalamusand olfactory degeneration in PT treated rats were 3.99% and 1.56% respectively. Saline treated animals served as controls and showed <0.3% changes in these brain areas. Quantification results of histopathology using image analysis were supported by the pathology score where the affected area was scored based on a severity scale. MRI T2 responses in hippocampus and cortex were compared to the toxicity in TMT treated animals as determined via histopathology quantification. Receiver Operating Characteristic (ROC) curves were generated to correlate histopathology and MRI responses. Correlation of MR imaging with quantitative histopathology analyses showed that MRI signals were in concordance with the histopathology and could effectively estimate loci and extent of neurodegeneration. Results suggest that MRI can be used as non‐invasive biomarker for the detection of drug‐induced neuropathology.Support or Funding InformationCenter for Drug Evaluation and Research ‐ Critical Path Award and National Center for Toxicological Research, Food and Drug AdministrationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.