Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Psychology

Date of Defense

4-24-2020

Graduate Advisor

Dr. George Taylor

Committee

Dr. George Taylor

Dr. Michael Griffin

Dr. Kevin Noguchi

Dr. Steven Mennerick

Abstract

The developing brain is susceptible to extensive neurotoxicity following exposure to sedative/anesthetic drugs (SADs). Every year hundreds of thousands of children around the world are exposed to SADs with no viable non-neurotoxic agents approved for clinical use. Allopregnanolone (AlloP) has well-established sedative effects in adults and neonates. AlloP and many SADs produce sedation/anesthesia through allosteric modulation of GABAA receptors, which is one of two principal mechanisms behind SAD-induced neurotoxicity. Evidence suggests AlloP has the unique capacity to regulate key apoptotic factors in adults and is widely involved with critical stages of neurodevelopment, indicating this neurosteroid might serve as a less neurotoxic sedative. Here, I showed the brexanolone (BRX) formulation of AlloP is more sedative than midazolam (MDZ). Lower doses of BRX had minimal impact on vital signs and produced no significant neurotoxic effect. Conversely, higher doses of BRX produced neurotoxicity, suggesting the apoptogenicity of BRX is dose dependent. Results for MDZ show far milder levels of sedation were obtainable until high doses. A significant neuroapoptotic response was induced at all sedative doses of MDZ. Prolonged light sedation similar to MDZ was obtained using BRX during continuous infusion. Although BRX appeared qualitatively less deleterious to heart and breath rate over time, 6-hour infusion of BRX induced a similar neurotoxic response compared to MDZ. These findings suggest low, sedative doses of BRX can be administered without gross impact to vital signs or neurotoxic consequences.

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