title: 3,6'-dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation.
abstract: 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.
authors: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
authors: Jeong Seon
authors: JS
authors: Yoon
authors: Jong-Hwan
authors: JH
authors: Lee
authors: David
authors: D
authors: Tweedie
authors: Mohamed R
authors: MR
authors: Mughal
authors: Srinivasulu
authors: S
authors: Chigurupati
authors: Nigel H
authors: NH
authors: Greig
authors: Mark P
authors: MP
authors: Mattson
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020521:Stroke / Q000150:complications* / Q000188:drug therapy*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C562075:3,6'-dithiothalidomide; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C404145:myelopoietin; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D013792:Thalidomide; D052247:Nitric Oxide Synthase Type II
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