Title : Memory impairment and dementia is enhanced with GABA-A receptor modulating steroids but antagonized by GABA-A receptor modulating steroid antagonists
Abstract:
Gamma-amino butyric acid (GABA) is the main inhibitory neurotransmitter in the brain and GABA-ergic transmission is important for the regulation of learning and memory. The progesterone metabolite allopregnanolone (Allo) is a potent positive GABA-A receptor modulating steroid (GAMS). In animal models, Allo impairs memory and deteriorates memory and learning in transgenic mice given continuously at doses corresponding to low-grade stress. In humans, Allo impairs episodic memory and a GAMS, medroxyprogesterone acetate treatment for four years doubled the frequency of dementia in elderly women. Disorders like hepatic encephalopathy and primary biliary cholangitis are associated with elevated Allo levels and impaired cognition, and increased fatigue. Methods: We have invented compounds that function as GABA-A receptor modulating steroid antagonists (GAMSA), but without intrinsic effects on the GABA-A receptors. They will be used to block the deteriorating effects of Allo. Results: The antagonistic effect is noted in most GABA-A subtypes investigated so far, especially the dominant GABA-A receptor subtype, alpha5, in the hippocampus and the subtype related to memory. In vivo, GAMSA inhibits Allo-induced anesthesia in rats, and sedation or saccadic eye velocity in humans. GAMSA, can inhibit Allo-induced memory disturbances in rats. A GAMSA (golexanolone, GR3027), restored learning and motor coordination in rat models of hepatic encephalopathy. GR3027 reverses neuroinflammation in the cerebellum and hippocampus in a rat model of neuroinflammation induced by hyperammonemia. In human’s, vigilance, cognition, and pathological EEG was improved in patients with hepatic encephalopathy when treated with GR3027. Conclusions: GAMSA seem to be possible to use as treatment for impaired cognition.
