Neurosteroid activity
Pregnenolone is an allosteric endocannabinoid, as it is a negative allosteric modulator of the CB1 receptor. Pregnenolone is involved in a natural negative feedback loop against CB1 receptor activation in animals. It prevents CB1 receptor agonists like tetrahydrocannabinol, the main active constituent in cannabis, from fully activating the CB1.A related compound AEF0117 has been derived from pregnenolone and is more specific for this type of activity.Pregnenolone has been found to bind with high, nanomolar affinity to microtubule-associated protein 2 (MAP2) in the brain.In contrast to pregnenolone, pregnenolone sulfate did not bind to microtubules. However, progesterone did and with similar affinity to pregnenolone, although unlike pregnenolone, it did not increase binding of MAP2 to tubulin. Pregnenolone was found to induce tubule polymerization in neuronal cultures and to increase neurite growth in PC12 cells treated with nerve growth factor. As such, pregnenolone may control formation and stabilization of microtubules in neurons and may affect both neural development during prenatal development and neural plasticity during aging.
Although pregnenolone itself does not possess these activities, its metabolite pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor as well as a positive allosteric modulator of the NMDA receptor.In addition, pregnenolone sulfate has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release.[12]
Nuclear receptor activity
Pregnenolone has been found to act as an agonist of the pregnane X receptor.Pregnenolone has no progestogenic, corticosteroid, estrogenic, androgenic, or antiandrogenic activity.
