Simvastatin Attenuates Stroke-induced Splenic Atrophy and Lung Susceptibility to Spontaneous Bacterial Infection in Mice

• Published in: Stroke (1970) Vol. 44; no. 4; pp. 1135 - 1143
• Main Authors: RONG JIN, XIAOLEI ZHU, LIN LIU, NANDA, Anil, NEIL GRANGER, D, GUOHONG LI
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.04.2013
• Subjects: Animals; Anticholesteremic Agents - pharmacology; Apoptosis; Atrophy - therapy; Bacterial Infections - drug therapy; Bacterial Infections - metabolism; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Brain Infarction; Disease Models, Animal; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Infarction, Middle Cerebral Artery; Infection; Interferon-gamma - metabolism; Lung - drug effects; Lung - microbiology; Lung - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Nervous system (semeiology, syndromes); Neurology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Simvastatin - pharmacology; Spleen - cytology; Spleen - drug effects; Spleen - pathology; Splenectomy; Stroke - complications; Stroke - drug therapy; Stroke - physiopathology; Vascular diseases and vascular malformations of the nervous system; Cardiovascular disease; Hypocholesterolemic agent; Vascular disease; HMG-CoA reductase inhibitor; Cerebrovascular disease; Stroke; Nervous system diseases; Immune response; Enzyme; spleen; Simvastatin; Rodentia; Enzyme inhibitor; Statin derivative; bacterial infection; Cerebral disorder; Infection; Vertebrata; Mammalia; Mouse; statin; Animal; Central nervous system disease; Bacteriosis; Brain ischemia; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Antilipemic agent
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/strokeaha.111.000633

Statins are widely used in the primary and secondary prevention of ischemic stroke, but their effects on stroke-induced immunodepression and poststroke infections are elusive. We investigated the effects of simvastatin treatment on stroke-induced splenic atrophy and lung susceptibility to bacterial infection in acute experimental stroke in mice. Ischemic stroke was induced by transient middle cerebral artery occlusion, followed by reperfusion. In some experiments, splenectomies were performed 2 weeks before middle cerebral artery occlusion. Animals were randomly assigned to sham and middle cerebral artery occlusion groups treated subcutaneously with vehicle or simvastatin (20 mg/kg per day). Brain infarction, neurological function, brain interferon-γ expression, splenic atrophy and apoptosis, and lung infection were examined. Simvastatin reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial antiapoptotic Bcl-2 expression and decreased proapoptotic Bax translocation from cytosol into mitochondria. Splenectomy reduced brain interferon-γ (3 days) and infarct size (5 days) after stroke, and these effects were reversed by adoptive transfer of splenocytes. Simvastatin inhibited brain interferon-γ (3 days) and reduced infarct volume and neurological deficits (5 days) after stroke, and these protective effects were observed not only in naive stroke mice but also in splenectomied stroke mice adoptively transferred with splenocytes. Simvastatin also decreased the stroke-associated lung susceptibility to spontaneous bacterial infection. Results provide the first direct experimental evidence that simvastatin ameliorates stroke-induced peripheral immunodepression by attenuating spleen atrophy and lung bacterial infection. These findings contribute to a better understanding of the beneficial effects of statins in the treatment of stroke.