3, 6′‐dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation. Issue 5 (13th February 2013)

• Record Type: Journal Article
• Authors: Yoon, Jeong Seon; Lee, Jong‐Hwan; Tweedie, David; Mughal, Mohamed R.; Chigurupati, Srinivasulu; Greig, Nigel H.; Mattson, Mark P.
• Is Part Of: Journal of neuroscience research. Volume 91:Issue 5(2013:May)
• Page Start: 671
• Page End: 680
• Publication Date: 2013-02-13
• Subjects: Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.23190
• Languages: English
• ISSNs: 0360-4012

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Tumor necrosis factor‐α (TNF) plays a prominent role in the brain damage and functional deficits that result from ischemic stroke. It was recently reported that the thalidomide analog 3, 6′‐dithiothalidomide (3, 6′‐DT) can selectively inhibit the synthesis of TNF in cultured cells. We therefore tested the therapeutic potential of 3, 6′‐DT in a mouse model of focal ischemic stroke. Administration of 3, 6′‐DT immediately prior to a stroke or within 3 hr after the stroke reduced infarct volume, neuronal death, and neurological deficits, whereas thalidomide was effective only when administered prior to stroke. Neuroprotection was accompanied by decreased inflammation; 3, 6′‐DT‐treated mice exhibited reduced expression of TNF, interleukin‐1β, and inducible nitric oxide synthase; reduced numbers of activated microglia/macrophages, astrocytes, and neutrophils; and reduced expression of intercellular adhesion molecule‐1 in the ischemic brain tissue. 3, 6′‐DT treatment attenuated stroke‐induced disruption of the blood–brain barrier by a mechanism that appears to involve suppression of matrix metalloproteinase‐9 and preservation of occludin. Treatment with 3, 6′‐DT did not reduce ischemic brain damage in mice lacking TNF receptors, consistent with a critical role for suppression of TNF production and TNF signaling in the therapeutic action of 3, 6′‐DT. These findings suggest that anti‐inflammatory mechanisms underlie the therapeutic actions of 3, 6‐DT in an animal model of stroke. © 2013 Wiley Periodicals, Inc.</p> </abstract>