Modelling oxidative stress in human hippocampal progenitor cells: insight into the pathogenesis of depression and antidepressants action

Abstract

Recent findings suggest that oxidative stress (OS) has an important role in the pathophysiology of major depressive disorder (MDD), however the underlying molecular mechanisms are still poorly understood. In this project, I set up an experimental in vitro OS model, using a human hippocampal progenitor cell line HPC0A07/03C capable of neurogenesis, to study molecular mechanisms potentially involved in the pathogenesis of this disorder and to evaluate the possible antioxidative properties of compounds with antidepressant properties.

Alterations of redox homeostasis were induced by treatment of the cells with a range of concentrations of tert-butyl hydroperoxide (t-BHP); higher doses were cytotoxic and lower doses led to major changes in neurogenesis and activation of the transcription factors Nrf2 and NF-κB in a dose-dependent manner. Potential redoxsignalling pathways involved in regulating neurogenesis were studied. Inhibition of the t-BHP–induced ERK1/2 activation abrogated the increased differentiation of progenitor cells into mature neurons observed upon oxidative stimulus. I tested various compounds for their antioxidative properties and found that the omega-3 fatty acid eicosapentaenoic acid (EPA), as well as the conventional antioxidants N-acetylcysteine (NAC) and glutathione (GSH) prevented the oxidative damage inflicted by t- BHP, with no effects observed for sertraline, venlafaxine, ketamine or docosahexaenoic acid (DHA). Both EPA and GSH differentially regulated the expression of genes involved in the OS response, including Keap1, HMOX1, SLC7A11 and SLC1A1.

Data obtained in this research project indicate that depending on the dose ROS can have detrimental effects on the viability and molecular profile of human hippocampal progenitor cells or facilitate neurobiological processes that are essential for normal cellular functioning and adaptation of the organism to environmental stimuli. Remarkably, EPA, known to exhibit antidepressant properties, elicited favourable effects in my OS in vitro model and appears to be a promising compound for further research in developing novel antidepressants targeting OS.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Patricia Zunszain (Supervisor) & Carmine Pariante (Supervisor)