Neurotrophic activity of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one in cultured central nervous system neurons

Endogenous neurotrophic factors are essential for the development and maintenance of the nervous system. This suggests their potential utilization as therapeutic agents for neurodegenerative diseases. However, the clinical use of these proteic factors is still restricted, and brings about undesirable consequences, including adverse side effects, and bioavailability and stability difficulties. Therefore, the development of low-molecular weight, non-proteic synthetic compounds with neurotrophic properties appears as a promising approach. The aim of this study was to explore the biological activity of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one (tCFA15), a trimethyl cyclohexenonic long-chain fatty alcohol. To this end, neurons from fetal rat cerebral hemispheres were cultured in the presence of increasing doses of tCFA15 ranging from 0.1 to 1000 nM. Quantification of cell numbers after 48-h culture showed that 100 nM tCFA15 induced a significant increase in the number of surviving cells. Measurement of total neurite length in microtubule-associated protein 2-positive cells also revealed a stimulatory effect in a wider range of concentrations. The extent of this neuritogenic action was similar to that induced by dibutyryl-cyclic AMP, a well-known neurite outgrowth stimulator, but used at much higher concentration (1 mM). Analysis of structure-activity relationships with different tCFA15 analogs and derivatives corroborated the neurotrophic activity. Taken together, these findings provide strong evidence that tCFA15 exhibits neurotrophic properties in vitro. (C) 2001 Elsevier Science B.V. All rights reserved.