Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Figure 4

De novo synthesis of allopregnanolone in the CNS. Cholesterol is transported across the mitochondrial membrane by the nucleoside transporter, translocator protein (TSPO) [60], and converted to pregnenolone within the mitochondria of glial cells, such as astrocytes, by side chain cleavage of cytochrome P450 (P450scc). Pregnenolone is subsequently converted to progesterone by 3β-hydroxysteroid dehydrogenases (3β-HSD). 5α-reductase type 1, converts Progesterone to 5α-dihydroprogesterone (5α-DHP), 5α-DHP is then converted to Allopregnanolone by the aldo-keto reductases enzyme, 3α-hydroxysteroid dehydrogenase (3α-HSD). Allopregnanolone activates GABA-A receptor intracellular sites by lateral diffusion in the neuronal membrane, where it acts as a potent allosteric modulator. Allopregnanolone can eventually be reconverted back to 5α-DHP by 3α-HSD [56].