title: Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion.
abstract: Cerebral small vessel disease (CSVD) is a pathological process leading to lacunar infarcts, leukoaraiosis and cerebral microbleeds. Dysfunction of the blood brain barrier (BBB) has been proposed as a mechanism in the progression cerebral small vessel disease. A rodent model commonly used to study some aspects of CSVD is bilateral common carotid artery occlusion (BCCAO) in the rat. In the present study it was determined that gait impairment, as determined by a tapered beam test, and BBB permeability increased following BCCAO. Cilostazol, a type III phosphodiesterase inhibitor, has been shown to have anti-apoptotic effects and prevent white matter vacuolation and rarefaction induced by BCCAO in rats. In this study the protective effect of cilostazol administration on the increase BBB permeability following BCCAO was determined as well as the effect on plasma levels of circulating microparticles (MPs), cerebral white matter rarefaction, glial activation and gait disturbance. The effect of cilostazol on in vitro endothelial barriers was also evaluated. Cilostazol treatment improved BBB permeability and reduced gait disturbance, visual impairment and microglial activation in optic tract following BCCAO in vivo. It also reduced the degree of cell death and the reduction in trans-endothelial electrical resistance (TEER) in artificial endothelial barriers in vitro induced by MP treatment of in vitro barriers.
authors.affiliation: Universiy of Ottawa, Neuroscience Graduate Program, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Edrissi
authors.affiliation: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Schock
authors.affiliation: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
authors.forename: Robert
authors.initials: R
authors.lastname: Cadonic
authors.affiliation: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
authors.forename: Antoine M
authors.initials: AM
authors.lastname: Hakim
authors.affiliation: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5. Electronic address: charliet@uottawa.ca.
authors.forename: Charlie S
authors.initials: CS
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D059345:Cerebral Small Vessel Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D000077407:Cilostazol; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020233:Gait Disorders, Neurologic / Q000150:complications / Q000517:prevention & control; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D065866:Optic Tract / Q000187:drug effects / Q000473:pathology; D010539:Permeability; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D013777:Tetrazoles / Q000008:administration & dosage*; D066127:White Matter / Q000187:drug effects* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol
keywords: Blood brain barrier permeability; Cerebral small vessel disease; Chronic cerebral hypoperfusion; Cilostazol; Circulating microparticles; Gait disturbance