3,6′-dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation

Jeong Seon Yoon, Jong Hwan Lee, David Tweedie, Mohamed R. Mughal, Srinivasulu Chigurupati, Nigel H. Greig, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)671-680
Number of pages10
JournalJournal of Neuroscience Research
Volume91
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • ICAM-1
  • Inflammation
  • Ischemia
  • Microglia
  • Neuroprotection
  • Occlusion
  • Stroke
  • Thalidomide
  • TNF

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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