title: The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis.
abstract: Blood-brain-barrier (BBB) disruption, inflammation and thrombosis are important steps in the pathophysiology of acute ischemic stroke but are still inaccessible to therapeutic interventions. Rolipram specifically inhibits the enzyme phosphodiesterase (PDE) 4 thereby preventing the inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to relief inflammation and BBB damage in a variety of neurological disorders. We investigated the therapeutic potential of rolipram in a model of brain ischemia/reperfusion injury in mice. Treatment with 10mg/kg rolipram, but not 2 mg/kg rolipram, 2 h after 60 min of transient middle cerebral artery occlusion (tMCAO) reduced infarct volumes by 50% and significantly improved clinical scores on day 1 compared with vehicle-treated controls. Rolipram maintained BBB function upon stroke as indicated by preserved expression of the tight junction proteins occludin and claudin-5. Accordingly, the formation of vascular brain edema was strongly attenuated in mice receiving rolipram. Moreover, rolipram reduced the invasion of neutrophils as well as the expression of the proinflammatory cytokines IL-1β and TNFα but increased the levels of TGFβ-1. Finally, rolipram exerted antithrombotic effects upon stroke and fewer neurons in the rolipram group underwent apoptosis. Rolipram is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.
authors.affiliation: University Clinic of Würzburg, Dept. of Neurology, Würzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.forename: Eva
authors.initials: E
authors.lastname: Göb
authors.forename: Nadine
authors.initials: N
authors.lastname: Heydenreich
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000517:prevention & control*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D020889:Rolipram / Q000627:therapeutic use*; D020521:Stroke / Q000150:complications / Q000209:etiology / Q000473:pathology*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D009419:Nerve Tissue Proteins; D062793:Occludin; D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram
keywords: Apoptosis; Blood–brain-barrier; Cytokines; Edema; Inflammation; Middle cerebral artery occlusion; Phosphodiesterase inhibitor; Rolipram; Stroke; Thrombosis