Fig. 1.

Biosynthesis of allopregnanolone.

Neurons can synthesize allopregnanolone de novo starting from cholesterol, which is recruited and translocated into the inner mitochondrial membrane preferentially in glial cells. Here, P450SCC metabolizes cholesterol into pregnenolone, the precursor of all neurosteroids. Pregnenolone is then taken up from neurons and is further metabolized into progesterone by 3β-HSD and progesterone can be further converted by the rate-limiting step enzyme, 5α-reductase type I into 5α-dihydroprogesterone (5α-pregnan-3,20-dione, 5α-DHP). Finally, 5α-DHP can be reduced into allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone) by the 3α-hydroxysteroid dehydrogenase (3α-HSD) enzyme. Allopregnanolone can eventually be reconverted into 5α-DHP.