Celine Girlanda-Junges

Cyclohexenonic Long-Chain Fatty Alcohols as Neuronal Growth Stimulators

Neurotrophic factors play an important role in the development and maintenance of neurons, thus providing a suitable therapeutic approach for the treatment of neurodegenerative diseases. However, their clinical use has revealed problematic because of a number of technical and biological disadvantages. Among the different strategies proposed to overcome such difficulties, the search for non-peptide substances with neurotrophic potential is giving promising results. Here we will expose major findings in this field, drawing special attention to cyclohexenonic long-chain fatty alcohols, a novel family of compounds that promote neuronal survival and neurite outgrowth.

Effect of cyclohexenonic long chain fatty alcohols on neurite outgrowth. Study on structure-activity relationship

Abstract Four series of long chain fatty alcohols bearing a cyclohexenone moiety in addition to a ω-alkanol side chain were synthesized using “Umpolung” reactivity strategy. Their effect on neurite outgrowth was evaluated by means of fetal rat neurons in culture. The length of the ω-hydroxy side chain is a crucial factor for biological activity.

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.

3-(15-Hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one and its effect on neuropeptide secretion.

The aim of the present study was to describe the synthesis of a trimethyl cyclohexenonic long chain fatty alcohol (t-CFA), and analyze its biological activity. Specifically, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one, the t-CFA containing 15 carbon atoms on the side chain (t-CFA n = 15) stimulated arginine vasopressin secretion in nerve terminals of the neurohypophysis. This effect was inhibited by extracellular calcium depletion, which suggests that t-CFA n = 15 stimulates neuropeptide secretion through a calcium-dependent exocytosis mechanism.