3-6--dithiothalidomide and Stroke

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.

Topics: Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Brain Infarction; Cell Death; Cytokines; Disease Models, Animal; Encephalitis; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Granulocyte Colony-Stimulating Factor; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Interleukin-3; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neutrophil Infiltration; Neutrophils; Nitric Oxide Synthase Type II; Recombinant Fusion Proteins; Stroke; Thalidomide; Tumor Necrosis Factor-alpha