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Neurosteroids are endogenous molecules that are enrichedin human brain. A number of neurosteroids demonstrate important pleiotropic actions that impact critical brainfunctions at physiologically relevant concentrations in rodent models. Pregnenolone (3β-hydroxypregn-5-en-20-one), also known as P5, is an endogenous steroid hormone.

In vitro: Pregnenolone is the precursor from which almost all of the other steroid hormones are made, including DHEA, testosterone, progesterone, the estrogens and cortisol. Pregnenolone also operates as a powerful neurosteroid in the brain, which modulates the transmission of messages from neuron to neuron and strongly influencing learning and memory processes [1].

In vivo: The ability of pregnenolone sulfate derivatives (PREGS) to modulate the age-induced learning impairment was tested in 16- month-old mice using the step-down type of passive avoidance. Decreased step-down latency was observed in the passive avoidance task in 16-month-old mice compared to 3-month-old mice, revealing retention deficits in old mice. Pretraining injections of PREGS dose-dependently improved the 24 h delay retention performances in this task in old mice [1].

Clinical trial: Human studies have reported improvement of learning and memory dysfunction after PREG administration to individuals with low PREGS levels, but other studies failed to detect significant cognitive effects of PREG administration [1].

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