GABA-A receptor modulating steroid antagonists decrease GABAergic tone, improve memory impairment, attenuates fatigue, and decrease neuroinflammation

Title : GABA-A receptor modulating steroid antagonists decrease GABAergic tone, improve memory impairment, attenuates fatigue, and decrease neuroinflammation

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 allosteric GABA-A Receptor Modulating Steroid (GAMS). In an Alzheimer transgenic mice model, Allo impairs memory and learning when given continuously at doses corresponding to low- grade stress. In humans, Allo impairs episodic memory and four years’ treatment of postmenopausal women with a GAMS, medroxyprogesterone acetate, doubled the frequency of dementia. CNS manifestations of advanced liver disease such as hepatic encephalopathy (HE) and/or primary biliary cholangitis, impaired cognition and increased fatigue are associated with elevated Allo levels. A GABA-A Receptor Modulating Steroid Antagonist (GAMSA; golexanolone - GR3027) can block the adverse effects of GAMS, especially on the GABA-A receptor subtype, alpha5, which is related to memory and located in the hippocampus. In healthy rats, golexanolone mitigates GAMS-induced anesthesia and impaired memory and, in healthy adults, reverses GAMS-induced sedation and impaired saccadic eye velocity. In rat models of HE, golexanolone restores learning and motor coordination and reverses neuroinflammation in the cerebellum and hippocampus. In humans with advanced liver disease and evidence of covert HE, golexanolone improves vigilance, cognition and pathological EEG patterns. These findings suggest that golexanolone shows promise as treatment for impaired cognition.

Audience Takeaway Notes:

• Positive GABA-A modulating steroids like allopregnanolone impairs memory.
• Several disorders with high allopregnanolone have fatigue and memory impairment.
• Antagonists to GABA-A modulating steroids can alleviate memory impairment.
• The antagonist Golexanolone reverses in addition neuroinflammation.

Biography:

Torbjorn C Backstrom currently works at the Clinical sciences, Umea Neurosteroid Research Center, Norrlands universitetssjukhus. Torbjorn does research in Neurology, Gynaecology and Obstetrics. Their current project is 'Satiety induction in polycystic ovarian syndrome and Prader Willi syndrome'.