mk-386 and Epilepsy

Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.

Topics: 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); 3-Hydroxysteroid Dehydrogenases; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Adolescent; Adult; Aged; Azasteroids; Brain; Child; Child, Preschool; Enzyme Inhibitors; Epilepsy; Female; Finasteride; Humans; Hydrogen-Ion Concentration; Infant; Isoenzymes; Male; Microsomes; Middle Aged; Neocortex; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sex Characteristics; Temporal Lobe; Tissue Distribution