The α5-GABA A R inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aβ.

Autor: Eimerbrink MJ; Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA., Pendry RJ; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA., Hodges SL; Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA., Wiles JD; UT Southwestern Medical Center, Dallas, TX 75390, USA., Peterman JL; Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA., White JD; Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA., Hayes HB; Department of Biology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA., Chumley MJ; Department of Biology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA., Boehm GW; Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA. Electronic address: g.boehm@tcu.edu.
Jazyk: angličtina
Zdroj: Behavioural brain research [Behav Brain Res] 2019 Feb 01; Vol. 359, pp. 871-877. Date of Electronic Publication: 2018 Jul 19.
DOI: 10.1016/j.bbr.2018.07.013
Abstrakt: Alzheimer's disease is marked by the presence of amyloid-beta (Aβ) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aβ in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aβ accumulation. Hippocampal Aβ was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aβ, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aβ, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aβ, and restore hippocampal BDNF expression.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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