Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine

The neurosteroid allopregnanolone (3 alpha,5 alpha-THP) is well characterized as a potentially therapeutic molecule which exerts important neurobiological actions including neuroprotective, antidepressant, anxiolytic, anesthetic and analgesic effects. We have recently observed that neurons and glial cells of the rat spinal cord (SC) contain various key steroiclogenic enzymes such as 5 alpha-reductase and 3 alpha-hydroxysteroid oxido-reductase which are crucial for 3 alpha,5 alpha-THP biosynthesis. Furthermore, we demonstrated that the rat SC actively produces 3 alpha,5 alpha-THP. As the key factors regulating neurosteroid production by nerve cells are unknown and because glycine is one of the pivotal inhibitory neurotransmitters; in the SC, we investigated glycine effects on 3 alpha,5 alpha-THP biosynthesis in the rat SC. Glycine markedly stimulated [H-3]-progesterone conversion into [H-3]3 alpha,5 alpha-THP by SC slices. The alkaloid strychnine, well-known as a glycine receptor (Gly-R) antagonist, blocked glycine stimulatory effect on 3 alpha,5 alpha-THP formation. Gelsemine, another alkaloid containing the same functional groups as strychnine, increased 3 alpha,5 alpha-THP synthesis. The stimulatory effects of glycine and gelsemine on 3 alpha,5 alpha-THP production were additive when the two drugs were combined. These results demonstrate that glycine and gelsemine, acting via Gly-R, upregulate 3 alpha,5 alpha-THP biosynthesis in the SC. The data also revealed a structure-activity relationship of the analogs strychnine and gelsemine on neurosteroidogenesis. Possibilities are opened for glycinergic agents and gelsemine utilization to stimulate selectively 3 alpha,5 alpha-THP biosynthetic pathways in diseases evoked by a decreased neurosteroidogenic activity of nerve cells. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.