Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-α in an animal model of inflamed Alzheimer’s disease brain

Neuroinflammatory responses caused by amyloid β (Aβ) peptide deposits are involved in the pathogenesis of Alzheimer’s disease (AD). A variety of anti-inflammatory agents have been investigated for treating AD, and  recently, drugs with anti-TNF-α activity, e.g., infliximab, etanercept and thalidomide, have been used in both animal models with AD-like conditions and humans with AD. Nfliximab and etanercept are not suitable as AD therapeutics since they are largely unable to cross the blood-brain barrier (BBB), which limits their use systemically for inflammatory conditions of the central nervous system (CNS). Thalidomide, which has anti-TNF-α effects, is a small molecule drug that can cross the BBB readily.

The overarching goal of this study was to investigate the anti-angiogenic and anti-inflammatory activities of thalidomide in a rat Aβ42-injection model of AD-like neuroinflammation, in which Aβ42is delivered directly into the rat hippocampus.  The data found that thalidomide significantly inhibited Aβ-peptide-induced vascular changes including endothelial cell proliferation, angiogenic activity and leakiness of the blood–brain In addition, thalidomide was found to block both microgliosis and astrogliosis, and thalidomide treatment was also associated with a significant reduction in hippocampal neuronal loss. The authors propose that these results suggest the utility thalidomide  in treating the inflamed AD brain.