3, 6-Dithiothalidomide protects the brain against ischemic stroke via an anti-inflammatory action

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIA	PHARM/PHYS-7

* FARE Award Winner

Authors

• J.S. Yoon
• D. Tweedie
• N.H. Greig
• M.P. Mattson

Abstract

Here we report that 3, 6-DT reduces neuronal loss and improves functional outcome in a mouse model of focal ischemic stroke. Administration of 3, 6-DT before or within 3 hours after the onset of ischemic brain injury reduces infarct volume, neuronal death and neurological deficits at 72h post-stroke. The neuroprotective effects of 3,6-DT were correlated with decreased levels of TNFalpha in the brains of both wild type and TNF receptor-deficient mice, whereas it only reduced brain damage in the wild type mice, consistent with a critical role for suppression of TNF production and TNF signaling in stroke pathogenesis. To understand the mechanism by which 3,6-DT protects neurons against ischemic injury, the involvement of inflammation in ischemic brain injury was examined. Mice treated with 3,6-DT exhibited: reduced the expression of TNF-alpha, IL-1beta, and iNOS; reduced activation of microglia/macrophage, astrocytes, neutrophils; and downregulation of the expression of ICAM-1 in the ischemic brain. In addition, 3,6-DT treatment attenuated BBB distruption following ischemic brain damage by reducing MMP-9 and by preventing the degradation of occludin. The number of apoptotic cells was also reduced by 3,6-DT treatment. These findings suggest that anti-inflammatory mechanism underlie the therapeutic actions of 3,6-DT in an animal model of stroke.

back to top