Abstract
We explored the utility of neural stem cells (NSCs) as an in vitro model for evaluating preclinical therapeutics in succinic semialdehyde dehydrogenase-deficient (SSADHD) mice. NSCs were obtained from aldh5a1+/+ and aldh5a1-/- mice (aldh5a1 = aldehyde dehydrogenase 5a1 = SSADH). Multiple parameters were evaluated including: (1) production of GHB (γ-hydroxybutyrate), the biochemical hallmark of SSADHD; (2) rescue from cell death with the dual mTOR (mechanistic target of rapamycin) inhibitor, XL-765, an agent previously shown to rescue aldh5a1-/- mice from premature lethality; (3) mitochondrial number, total reactive oxygen species, and mitochondrial superoxide production, all previously documented as abnormal in aldh5a1-/- mice; (4) total ATP levels and ATP consumption; and (5) selected gene expression profiles associated with epilepsy, a prominent feature in both experimental and human SSADHD. Patterns of dysfunction were observed in all of these parameters and mirrored earlier findings in aldh5a1-/- mice. Patterns of dysregulated gene expression between hypothalamus and NSCs centered on ion channels, GABAergic receptors, and inflammation, suggesting novel pathomechanisms as well as a developmental ontogeny for gene expression potentially associated with the murine epileptic phenotype. The NSC model of SSADHD will be valuable in providing a first-tier screen for centrally-acting therapeutics and prioritizing therapeutic concepts of preclinical animal studies applicable to SSADHD.
Highlights
Our findings indicate that aldh5a1-/- neural stem cells (NSCs) express most of the markers of the succinic semialdehyde dehydrogenase-deficient (SSADHD) mouse brain and hold significant value in the screening of potential therapeutics applicable to human SSADHD
We have undertaken the development of NSCs from aldh5a1-/- mice as a potential in vitro modeling system
The utility of such a model is many-fold: (1) less expensive than modeling in aldh5a1-/- mice, whose lifespan is truncated; (2) the capacity for high-throughput analysis; (3) bypass of peripheral metabolic processes with focus on neuropharmacology; (4) potential to “prioritize” therapeutics applicable to SSADHD to move forward to preclinical animal studies; and (5) in vitro modeling of the developing brain, with ability to study the impact of candidate drugs on neurogenesis
Summary
Our objective was to develop and undertake preliminary validation of an in vitro model system in which to study preclinical therapeutics applicable to SSADHD
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