The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis

被引:64
|
作者
Kraft, Peter [1 ]
Schwarz, Tobias [1 ]
Goeb, Eva [1 ]
Heydenreich, Nadine [1 ]
Brede, Marc [2 ]
Meuth, Sven G. [3 ,4 ]
Kleinschnitz, Christoph [1 ]
机构
[1] Univ Clin Wurzburg, Dept Neurol, D-97080 Wurzburg, Germany
[2] Univ Clin Wurzburg, Dept Anesthesiol & Crit Care, D-97080 Wurzburg, Germany
[3] Univ Munster, Dept Neurol Inflammatory Disorders Nervous Syst &, D-48149 Munster, Germany
[4] Univ Munster, Inst Physiol, D-48149 Munster, Germany
关键词
Blood-brain-barrier; Phosphodiesterase inhibitor; Rolipram; Inflammation; Middle cerebral artery occlusion; Edema; Apoptosis; Thrombosis; Cytokines; Stroke; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PLASMINOGEN ACTIVATOR EXPRESSION; CEREBRAL-ARTERY OCCLUSION; CYCLIC-AMP; FUNCTIONAL RECOVERY; CYTOKINE PRODUCTION; REPERFUSION INJURY; TNF-ALPHA; CAMP; RAT;
D O I
10.1016/j.expneurol.2013.03.026
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 beta and TNF alpha but increased the levels of TGF beta-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. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:80 / 90
页数:11
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