Rat white matter injury model induced by endothelin-1 injection: technical modification and pathological evaluation.
White matter injury is an important cause of functional disability of the brain. We comprehensively analyzed a modified endothelin-1 (ET‑1) injection-induced white matter injury model in the rat which is very valuable for investigating the underlying mechanisms of subcortical ischemic stroke. ET-1 was stereotactically injected into the internal capsule of the rat. To avoid complications with leakage of ET-1 into the lateral ventricle, the safest trajectory angle to the target was established. Rats with white matter injury were extensively evaluated for structural changes and functional sequelae, using motor function tests, magnetic resonance (MR) imaging, histopathology evolution, volume estimation of the lesion, and neuroanatomical identification of affected neurons using the retrograde tracer hydroxystilbamidine. Optimization of the trajectory of the ET-1 injection needle provided excellent survival rate. MR imaging visualized the white matter injury 2 days after surgery. Motor function deficit appeared temporarily after the operation. Histological studies confirmed damage of axons and myelin sheaths followed by inflammatory reaction and gliosis similar to lacunar infarction, with lesion volume of less than 1% of the whole brain. Hydroxystilbamidine injected into the lesion revealed wide spatial distribution of the affected neuronal population. Compared with prior ET-1 injection models, this method induced standardized amount of white matter damage and temporary motor function deficit in a reproducible and safe manner. The present model is valuable for studying the pathophysiology of not only ischemia, but a broader set of white matter damage conditions in the lissencephalic brain.
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hideaki
H
Ono
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. hiimai-nsu@umin.ac.jp.
Hideaki
H
Imai
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Satoru
S
Miyawaki
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hirofumi
H
Nakatomi
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nobuhito
N
Saito
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000378:metabolism; D019332:Endothelin-1 / Q000633:toxicity*; D007839:Functional Laterality / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020772:Internal Capsule / Q000187:drug effects; D056784:Leukoencephalopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008279:Magnetic Resonance Imaging; D009460:Neurologic Examination; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013266:Stilbamidines / Q000493:pharmacokinetics; D013550:Swimming / Q000523:psychology; D013997:Time Factors
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D016564:Amyloid beta-Protein Precursor; D053331:Ectodysplasins; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D013266:Stilbamidines