tCFA15

tCFA15, a trimethyl cyclohexenonic long-chain fatty alcohol, affects neural stem fate and differentiation by modulating Notch1 activity

We have investigated the effects of tCFA15, a non-peptidic compound, on the differentiation of neural stem cell-derived neurospheres, and have found that tCFA15 promotes their differentiation into neurons and reduces their differentiation into astrocytes, in a dose-dependent manner. This response is reminiscent of that resulting from the loss-of-function of Notch signaling after inactivation of the Delta-like 1 (Dll1) gene. Further analysis of the expression of genes from the Notch pathway by reverse transcriptase-PCR revealed that tCFA15 treatment results in a consistent decrease in the level of Notch1 mRNA. We have confirmed this result in other cell lines and propose that it reflects a general effect of the tCFA15 molecule. We discuss the implications of this finding with respect to regulation of Notch activity in neural stem cells, and the possible use of tCFA15 as a therapeutic tool for various pathologies that result from impairment of Notch signaling.

Effects of cyclohexanonic long-chain fatty alcohol, tCFA15 on amino acids in diabetic rat brain: a preliminary study

The aim of this study was to evaluate the effects of streptozotocin-induced type 1diabetes and a subchronic treatment with cyclohexanonic long-chain fatty alcohol, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (tCFA15) on contents of amino acids including aspartate, glutamate, glutamine, GABA, glycine, taurine, alanine, serine, threonine, and arginine in the prefrontal cortex, hippocampus and striatum. Levels of glutamate, threonine, taurine, alanine, arginine, and the ratio of glutamate/glutamine were altered region-differently in the brain of diabetic rats. However, tCFA15 region-specifically antagonized the changes in taurine and arginine levels and the ratio of glutamate/glutamine. The alteration in glutamate/glutamine ratio may indicate that experimental models of type 1 diabetes have abnormalities of neuron-gria interaction in brain.

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.

Beneficial action of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one, a novel long-chain fatty alcohol, on diabetic hypoalgesia and neuropathic hyperalgesia

The effects of 2,4,4-trimethyl-3-(15-hydroxypentadecyl)-2-cyclohexen-1-one (tCFA15) on diabetic hypoalgesia and neuropathic hyperalgesia were examined. Treatments of streptozotocin (STZ)-pretreated mice with tCFA15 (8 - 40 mg/kg, i.p.) for 7 days significantly reversed the depressed inflammatory nociceptive licking response in the formalin test. In addition, similar drug treatments and dosing in 7-day postoperative neuropathic pain model rats (prepared by the method of Bennett and Xie) yielded a similarly favorable outcome by significantly reversing decreased nociceptive thresholds in the paw pressure test. These results suggest that tCFA15 may have the potential to normalize sensory nerve abnormalities induced in experimental diabetes and nerve injury.

Counteraction of axonal growth inhibitory properties of Semaphorin 3A and myelin-associated proteins by a synthetic neurotrophic compound

One of the reasons for the lack of nerve regeneration in the CNS is the formation of a glial scar over-expressing multiple inhibitory factors including myelin-associated proteins and members of the Semaphorin family. Innovative therapeutic strategies must stimulate axon extension across the lesion site despite this inhibitory molecular barrier. We recently developed a synthetic neurotrophic compound combining an omega-alkanol with a retinol-like cycle (3-(15-hydroxy-pentadecyl)-2,4,4,-trimethyl-cyclohexen-2-one (tCFA15)). Here, we demonstrate that tCFA15 is able to promote cortical axon outgrowth in vitro even in the presence of the inhibitory Semaphorin 3A and myelin extracts. This growth-promoting effect is selectively observed in axons and requires multiple growth-associated intracellular pathways. Our results illustrate the potential use of synthetic neurotrophic compounds to promote nerve regeneration by counteracting the axonal growth inhibition triggered by glial scar-associated inhibitory factors.