title: Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain.
abstract: Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimura
authors.forename: Terubumi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hideo
authors.initials: H
authors.lastname: Mori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Takao
authors.initials: T
authors.lastname: Urabe
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D000077407:Cilostazol; D015140:Dementia, Vascular / Q000201:enzymology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D058987:Phosphodiesterase 3 Inhibitors; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol