GABA-A receptor modulating steroids impair memory and promotes dementia but can be antagonized with GABA-A receptor modulating steroid antagonists.

Title : GABA-A receptor modulating steroids impair memory and promotes dementia but can be antagonized with GABA-A receptor modulating steroid antagonists.

Abstract:

GABA-ergic transmission is shown to be of importance for regulation of mood, memory, and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders like premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory, and increased food intake in some individuals. This is surprising as Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that in certain individuals GABAA receptor active compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations while anxiolytic at high levels. In Alzheimer transgenic mice continuous allo in low stress concentrations deteriorated the dementia progress. We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA), but without any effects by its own on the GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated so far. In vivo, Isoallo inhibits Allo-induced anesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo has been studied in women with PMDD. In two phase II studies, Isoallo (Sepranolone) injections significantly ameliorated negative mood in women with PMDD compared with placebo. One GAMSA, UC1011, could inhibit Allo induced memory disturbances in rats. A GAMSA for oral administration have also been developed, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In human’s, vigilance, cognition, and pathological EEG was improved in patients with hepatic encephalopathy when treated with GR3027.

Biography:

Torbjörn Bäckström, MD and PhD, senior professor at the Department of Clinical Science, Obstetrics and Gynecology, Umeå University as well as head of the Umeå Neurosteroid Research Center, started Umecrine Mood together with the Karolinska Institutet innovation system in 2006 and the company became Asarina Pharma in 2015. Professor Bäckström's main focus of research since 1972 is the effect of sex and stress hormones on the brain and in particular on the GABA-system, and conditions induced by these hormones. He has published more than 400 scientific publications within this area and he is a frequently invited key-note speaker at scientific meetings around the world. In 1989 professor Bäckström served several years on the scientific advisory board of the pharmaceutical company, CoCensys in the US, a company based on his own and the research of professor Kelvin Gee from University of California. Several active compounds were developed and one of these is currently in phase III of clinical development. CoCensys, was listed on the NASDAQ stock market until 1994, when it was sold to a larger pharmaceutical company.