Abstract
One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival, and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration. Here, we establish the existence of a unique family of methylene-cycloalkylacetate-based molecules (MCAs) that interface with neuronal cell properties and operate as acceptable pharmacophores for a novel neurotropic (neurite outgrowth inducing) lead compounds. Using an established PC12 cell bioassay, we investigated the neurotropic effect of methylene-cycloalkylacetate compounds by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by using a light microscope camera, and digitized photographs were analyzed for compound-induced neurotropic activity using an NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. The discovered lead compounds need further mechanistic investigation and may be improved toward development of a neurotropic drug.
| Original language | English |
|---|---|
| Pages (from-to) | 691-698 |
| Number of pages | 8 |
| Journal | ACS Chemical Neuroscience |
| Volume | 9 |
| Issue number | 4 |
| DOIs | |
| State | Published - 18 Apr 2018 |
Bibliographical note
Funding Information:*Mailing address: School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail: [email protected]. Tel: +972-2-6758729. Fax: +972-2-6757490. *Mailing address: School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail: [email protected]. Tel: +972-2-6757032. Fax: +972-2-6757076. ORCID Dmitry Tsvelikhovsky: 0000-0002-1581-5291 Author Contributions D.L. and D.H. designed and conducted the experiments, and performed data analysis. D.L. synthesized and characterized the compounds. A.L. helped to conduct the experiments. D.T. and P.L. provided insight into interpretation of the results and wrote the manuscript. Funding P.L. holds the Jacob Gitlin Chair in Physiology and is affiliated and supported by David R. Bloom Center for Pharmacy and Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel. D.T. gratefully acknowledge the Yissum- HUJI for a Technology Transfer Grant. The research project was also financially supported by the State of Lower Saxony, Hannover, Germany. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2017 American Chemical Society.