A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease
The overarching goal of this study was to improve the potency and pharmacokinetic properties of curcumin, and to test the improved analogs for efficacy in the APP/PS1 mouse model of AD. To this end, the authors synthesized a series of hybrid molecules between curcumin and cyclohexyl-bisphenol A (CBA), a compound that has neurotrophic activity which curcumin lacks. The best compound was CNB-001, a molecule that has improved stability over curcumin and that is neuroprotective in multiple neurotoxicity assays in which curcumin is inactive. Next, the authors generated a large number of derivatives of CNB-001 and selected the best compound on the basis of activity in our multiple toxicity assays. The result was a much more potent molecule- J147. J147 was found to be broadly neuroprotective and possess memory enhancing activity in normal animals, and the ability to prevent memory deficits in AD transgenic mice. The neurotrophic and memory-enhancing activities of J147 are associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, the enhancement of LTP, synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ1–42 and Aβ1–40. These pleiotrophic effects of a single molecule suggest that J147 has potential for the treatment of AD.