The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis
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- 作者：Peter Kraft ; Tobias Schwarz ; Eva G?b ; Nadine Heydenreich ; Marc Brede ; Sven G. Meuth ; Christoph Kleinschnitz
- 关键词：Blood&ndash ; brain-barrier ; Phosphodiesterase inhibitor ; Rolipram ; Inflammation ; Middle cerebral artery occlusion ; Edema ; Apoptosis ; Thrombosis ; Cytokines ; Stroke
- 刊名：Experimental Neurology
- 出版年：2013
- 出版时间：September, 2013
- 年：2013
- 卷：247
- 期：Complete
- 页码：80-90
- 全文大小：1208 K
文摘
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 10 mg/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-1¦Â and TNF¦Á but increased the levels of TGF¦Â-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.