Torbjörn Bäckström | GABA-A receptor modulating steroids enhance

Torbjörn Bäckström, MD. PhD., Umeå University, Umeå, Sweden Title: GABA-A receptor modulating steroids enhance dementia, but antagonists inhibit inflammation and improve memory. 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. Sex and stress neurosteroids like allopregnanolone, tetrahydrodeoxycorticosterone and androsterone are a potent positive GABA-A receptor modulating steroids (PAM). In animal models, Allo impairs memory and deteriorates memory and learning in Altheimer transgenic mice given continuously at doses corresponding to low-grade stress. In humans, Allo impairs episodic memory and a PAM, medroxyprogesterone acetate used for treatment of menopausal symptoms 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. We have invented compounds that function as GABA-A receptor modulating steroid antagonists (GAMSA), but without intrinsic effects on the GABA-A receptors. They can block the deteriorating effects of PAMs. The antagonistic effect is noted in most GABA-A subtypes investigated, especially the GABA-A receptor subtype, alpha5, in the hippocampus that is related to memory. In vivo, GAMSA inhibits PAM-induced anesthesia in rats, sedation and saccadic eye velocity in humans and inhibits PAM-induced memory disturbances in rats. In one clinical trial GAMSA (golexanolone), restored learning and motor coordination in rat models of hepatic encephalopathy in addition it reverses neuroinflammation in the cerebellum and hippocampus in a rat model of neuroinflammation. In human’s, vigilance, cognition, and pathological EEG was improved in patients with hepatic encephalopathy when treated with golexanolone. Conclusion: GAMSA seem to be possible to use as treatment for impaired cognition. References: Bengtsson, et al. Neurobiology of Stress. 2020;12:100206:1-20. Johansson et al. Psychopharmacology. 2018;235(5):1533-1543 Mincheva et al. Neurosci Ther. 2022;Jul26. doi:10.1111/cns.13926. Montagnese et al. J. of Hepatol, 2021;Jul;75(1):98-107doi:10.1016/j.jhep.2021.03.012 Bäckström et al. Neuroscience, Biobehavioral Reviews 2024;161:105668, doi: 10.1016/j.neubiorev. Bäckström et al. Journal of Internal Medicine, 2023;0;1–14,doi:10.1111/joim.13705 Llansola et al., Pharmaceuticals 2025, 18, 1757. https://doi.org/10.3390/ph18111757 #ISAD2026 #Alzheimers #Dementia #AlzheimersDisease #DementiaResearch #AlzheimersResearch #Neuroscience #NeurodegenerativeDiseases #BrainHealth #Neuroinflammation #Amyloid #TauProtein #Biomarkers #ClinicalResearch #ScientificConference #MedicalConference #InternationalConference #ResearchCollaboration #Innovinc #InnovincConferences #InnovincInternational #ParisConference