Following from positive phase II results, the announcement earlier this year that Dimebon (latrepirdine) failed to show a significant effect in a phase III clinical trial in Alzheimer’s patients was a major blow to patients, families and doctors. A study by researchers at UT Southwestern Medical Center has now shown that Dimebon can increase neurogenesis in adult rodent brains and have identified other, more potent compounds.
An in vivo screen of 1000 small molecules in adult mice identified eight compounds that were able to enhance neuron formation in the subgranular zone of the hippocampal dentate gyrus. One of the compounds, P7C3, was selected for further study on the basis of favourable ADME predictions. Daily administration of P7C3 to aged rats for 7 days was shown to enhance hippocampal neurogenesis relative to control animals and, after 2 months, treated rats performed significantly better in the Morris water maze test which provides a measure of learning and memory.
P7C3 exerts its proneurogenic effects by protecting newborn neurons from apoptosis and the team next compared the activity of P7C3 with that of Dimebon, which is also believed to have anti-apoptotic activity. Dimebon was found to be proneurogenic in vivo, albeit at levels 10-30 times higher than P7C3, raising the possibility that the two compounds may share a common mechanistic pathway. Although this idea can only be rigorously tested after identification of the molecular target(s), the study raises the hope that more potent analogues of Dimebon with improved clinical efficacy could be identified and also provides appropriate assays.
The study is published in the journal Cell.