Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat

Hideaki Wakita, Hidekazu Tomimoto, Ichiro Akiguchi, Jin Xi Lin, Masafumi Ihara, Ryo Ohtani, Masunari Shibata

Research output: Contribution to journalArticle

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Abstract

Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-α is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-α production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg ibudilast exhibited percent reduction of the white matter lesions ranging between 50% and 70%, which was more effective than 30 mg/kg ibudilast (p<0.05). The TNF-α immunoreactive glia decreased in number in the 60 mg/kg ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of ibudilast against cerebrovascular white matter lesions and suggest a potential use for ibudilast in the treatment of vascular dementia.

Original languageEnglish
Pages (from-to)53-59
Number of pages7
JournalBrain Research
Volume992
Issue number1
DOIs
Publication statusPublished - 28-11-2003

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Phosphodiesterase Inhibitors
Vascular Dementia
Tumor Necrosis Factor-alpha
Common Carotid Artery
ibudilast
White Matter
Internal Capsule
Histocompatibility Antigens
Corpus Callosum
Microglia
Myelin Sheath
Major Histocompatibility Complex
Neuroglia
Cyclic AMP
Ligation
Blood Vessels
Oral Administration

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Wakita, Hideaki ; Tomimoto, Hidekazu ; Akiguchi, Ichiro ; Lin, Jin Xi ; Ihara, Masafumi ; Ohtani, Ryo ; Shibata, Masunari. / Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. In: Brain Research. 2003 ; Vol. 992, No. 1. pp. 53-59.
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abstract = "Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-α is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-α production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg ibudilast exhibited percent reduction of the white matter lesions ranging between 50{\%} and 70{\%}, which was more effective than 30 mg/kg ibudilast (p<0.05). The TNF-α immunoreactive glia decreased in number in the 60 mg/kg ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of ibudilast against cerebrovascular white matter lesions and suggest a potential use for ibudilast in the treatment of vascular dementia.",
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Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. / Wakita, Hideaki; Tomimoto, Hidekazu; Akiguchi, Ichiro; Lin, Jin Xi; Ihara, Masafumi; Ohtani, Ryo; Shibata, Masunari.

In: Brain Research, Vol. 992, No. 1, 28.11.2003, p. 53-59.

Research output: Contribution to journalArticle

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