Small Molecule TGF-beta Mimetics as Potential Neuroprotective Factors

Hui      Zhang; Kun      Zou; Ina      Tesseur; Tony      Wyss-Coray

Abstract

Neurodegenerative and dementing illnesses are becoming an increasing social and economical burden as the number of older people continues to grow in industrialized countries. Current knowledge of the processes leading to these diseases is still limited, and very few effective treatments are available. Because neurodegeneration is associated with an activation of injury and innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-β1 is an organizer of the brains response to injury and is known to be neuroprotective. Previous studies from our lab also showed that TGF-β1 can reduce accumulation of β-amyloid peptide (Aβ), which appears to be central to Alzheimers disease (AD) pathogenesis, and we therefore initiated a search for small molecule chemical compounds that could mimic this effect. We report here the identification of several such TGF-β mimetics detected in an in vitro screen of a library with 5000 chemically diverse compounds. If active in vivo, these mimetics could be developed into candidates for the treatment of neurodegeneration.

Keywords: neurodegenerative disorder, phosphorylation, neurons, cortex, transgenic mice, smad-binding element (sbe), gene transcription, thymidine kinase, rat astrocytoma cells