Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures. ACTH and Dexamethasone induce different pathway enrichments
Abstract number :
2.422
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2232999
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:29 AM
Authors :
Mohamed Ouardouz, PhD – Nemours Foudation; Jeffrey Brabec, PhD – University of Vermont; Matthew Mahoney, PhD – The Jackson Laboratory; Rodney Scott, MD PhD – Division of Neuroscience – Nemours Children’s Health,; Amanda Hernan, PhD – Division of Neuroscience – Nemours Children’s Health
This is a Late Breaking abstract
Rationale: Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients’ quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not.
Methods: Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle- ELS. Rat pups were subjected to 60 flurothyl seizures (6 seizures per day at one hour interval) from P5 to P15. One day after the last seizure induction, brains were removed, and the hippocampus and PFC were dissected and flash frozen in a dry ice ethanol bath and stored in an Eppendorf tube at -80° C until processed for RNA extraction. After, RNA was sequenced, a differential expression analysis was performed using generalized estimating equations.
Results: We observed that ACTH treatment resulted in a gene expression pattern with fewer DEGs compared to Controls than Dex. Additionally, when compared to vehicle-treated animals that underwent ELS, animals treated with ACTH and Control animals shared a much larger proportion of DEGs than Dex and Control animals. This, despite Dex’s larger proportion of DEGs compared to VEH, suggests that ACTH treatment normalizes gene expression in a more targeted way.
Conclusions: Our results in this study indicate that the genes and pathways ACTH influences help push gene expression in the brain back to a normal state of expression by upregulating genes which support homeostatic balance and downregulating those which might contribute to excitotoxic cell damage post-ELS; in support of the more targeted and brain-specific differential gene expression, we suggest that ACTH may exert its differential actions through pathways that are dependent on melanocortin receptors in the brain.
Funding: JLB and JMM were funded by an NIH NIGMS award (5P20GM130454-02). AEH was funded by an NIH NINDS award (7K22NS104230). RCS and MO were funded by an NIH NINDS award (1R21NS117112-01). Investigator-initiated grant from Mallinckrodt pharmaceuticals.
Neurophysiology