title: Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat.
abstract: Cerebral white matter (WM) lesions are observed frequently in human ischemic cerebrovascular disease and have been thought to contribute to cognitive impairment. This type of lesion can be experimentally induced in rat brains under chronic cerebral hypoperfusion by the permanent occlusion of both common carotid arteries. However, it remains uncertain whether chronic ischemia can damage both the gray and white matter, and whether it can induce demyelination with or without axonal damage. Therefore, we examined axonal damage using immunohistochemistry for the amyloid beta/A4 precursor protein (APP), chromogranin A (CgA) and demyelination using immunohistochemistry for the encephalitogenic peptide (EP) in this model. Severe WM lesions such as vacuolation and the loss of nerve fibers appeared in the optic nerve and optic tract after 3 days of ligation, and less intense changes were observed in the corpus callosum, internal capsule, and fiber bundles of the caudoputamen after 7 days with Klüver-Barrera and Bielschowsky staining. These WM lesions persisted even after 30 days. The APP, CgA, and EP-immunopositive fibers increased in number from 1 to 30 days after the ligation in the following WM regions: the optic nerve, optic tract, corpus callosum, internal capsule, and fiber bundles of the caudoputamen. In contrast, only a few APP, CgA, or EP-immunopositive fibers were detected in the gray matter regions, including the cerebral cortex and hippocampus. These results indicate that the WM is more susceptible to chronic cerebral hypoperfusion than the gray matter, with an involvement of both axonal and myelin components. Furthermore, immunohistochemistry for APP, CgA, and EP is far superior to routine histological staining in sensitivity and may become a useful tool to investigate WM lesions caused by various pathoetiologies.
authors.affiliation: Department of Neurology, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. wakita@kuhp.kyoto-u.ac.jp
authors.forename: Hideaki
authors.initials: H
authors.lastname: Wakita
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Akiguchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Matsuo
authors.forename: Jin Xi
authors.initials: JX
authors.lastname: Lin
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D014855:Wallerian Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053379:Chromogranin A; D002864:Chromogranins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C110235:myelin basic protein 68-86