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

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-alpha 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)-alpha 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-alpha inummoreactive 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. (C) 2003 Elsevier B.V. All rights reserved.