Browsing by Subject "Neuroactive steroids"

Now showing 1 - 3 of 3
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    GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors
    (Elsevier, 2022-06) Cerne, Rok; Lippa, Arnold; Poe, Michael M.; Smith, Jodi L.; Jin, Xiaoming; Ping, Xingjie; Golani, Lalit K.; Cook, James M.; Witkin, Jeffrey M.; Anatomy and Cell Biology, School of Medicine
    Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.
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    GABAkines – Advances in the Discovery, Development, and Commercialization of Positive Allosteric Modulators of GABAA Receptors
    (Elsevier, 2022) Cerne, Rok; Lippa, Arnold; Poe, Michael M.; Smith, Jodi L.; Jin, Xiaoming; Ping, Xingjie; Golani, Lalit K.; Cook, James M.; Witkin, Jeffrey M.; Anatomy, Cell Biology and Physiology, School of Medicine
    Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The present review focuses on the new GABAkines in. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.
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    White Matter Microstructure Is Associated with Serum Neuroactive Steroids and Psychological Functioning
    (Mary Ann Liebert, 2023) Umminger, Lisa F.; Rojczyk, Philine; Seitz-Holland, Johanna; Sollmann, Nico; Kaufmann, Elisabeth; Kinzel, Philipp; Zhang, Fan; Kochsiek, Janna; Langhein, Mina; Kim, Cara L.; Wiegand, Tim L. T.; Kilts, Jason D.; Naylor, Jennifer C.; Grant, Gerald A.; Rathi, Yogesh; Coleman, Michael J.; Bouix, Sylvain; Tripodis, Yorghos; Pasternak, Ofer; George, Mark S.; McAllister, Thomas W.; Zafonte, Ross; Stein, Murray B.; O'Donnell, Lauren J.; Marx, Christine E.; Shenton, Martha E.; Koerte, Inga K.; Psychiatry, School of Medicine
    Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FAT (β = 0.24, t = 3.05, p = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity (β = 0.00, t = 2.50, p = 0.027), although an mTBI diagnosis alone did not significantly impact this association (p = 0.088). There was no significant association between PREGNE and FAT (p = 0.380). Importantly, lower FAT is associated with poor psychological functioning (β = -0.19, t = -2.35, p = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.