Neurosteroid Biosynthetic Pathway Changes in Substantia Nigra and Caudate Nucleus in Parkinson's Disease

Abstract

There is emerging evidence from animal studies for a neuroprotective role of sex steroids in neurodegenerative diseases, but studies in human brain are lacking. We have carried out an extensive study of the neurosteroid biosynthetic pathways in substantia nigra (SN), caudate nucleus (CN) and putamen (PU) of 7 Parkinson's disease (PD) patients and 7 matched controls. The mRNA levels of 37 genes including neurosteroid biosynthetic enzymes, hormone receptors and the neurosteroid-modulated gamma-amino-butyric acid -A (GABA-A) receptor subunits were analyzed by quantitative PCR (qPCR). In the SN, we found downregulation of 5alpha-reductase type 1 (5alpha-R1), sulfotransferase 2B1 (SULT2B1) and some GABA-A receptor subunits (alpha4, beta1) while in the CN, upregulation of 3alpha-hydroxysteroid dehydrogenase type 3 (3alpha-HSD3) and alpha4 GABA-A receptor subunit (22-fold) was observed. No significant differences were found in the PU. These data imply an involvement of pregnane steroids and changes in GABAergic neurotransmission in the neurodegenerative process and suggest that neurosteroids may deserve further investigation as potential therapeutic agents in PD.