Abstract

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin treatment significantly reduced the number of Fluoro-Jade B-positive cells and caspase-3 activation within the hippocampus of CRS-treated mice. Moreover, rubrofusarin treatment significantly increased the number of newborn neurons in the hippocampus of CRS-treated mice. CRS induced activation of glycogen synthase kinase-3β and regulated development and DNA damage responses, and reductions in the extracellular-signal-regulated kinase pathway activity were also reversed by rubrofusarin treatment. Microglial activation and inflammasome markers, including nod-like receptor family pyrin domain containing 3 and adaptor protein apoptosis-associated speck-like protein containing CARD, which were induced by CRS, were ameliorated by rubrofusarin. Synaptic plasticity dysfunction within the hippocampus was also rescued by rubrofusarin treatment. Within in vitro experiments, rubrofusarin blocked corticosterone-induced long-term potentiation impairments. These were blocked by LY294002, which is an Akt inhibitor. Finally, we found that the antidepressant effects of rubrofusarin were blocked by an intracerebroventricular injection of LY294002. These results suggest that rubrofusarin ameliorated CRS-induced depressive symptoms through PI3K/Akt signaling.

Highlights

  • Exposure to stress is known to affect various brain functions [1,2]

  • The chronic restraint stress (CRS) group showed a significantly lower discrimination index compared to the control group, suggesting potential impairment in recognition memory

  • RF (30 mg/kg) or FLX (10 mg/kg)-treated CRS groups showed significantly higher discrimination ratios compared to the CRS group (F4,45 = 5.648, p < 0.05, n = 10/group, Figure 1E)

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Summary

Introduction

Exposure to stress is known to affect various brain functions [1,2]. For instance, acute stress induces norepinephrine and glucocorticoid release from the adrenal glands, causing bodily changes, allowing individuals to adaptively respond to the stressor [3,4,5]. Most frequently prescribed antidepressants currently include Prozac (fluoxetine) and Zoloft (sertraline) These are selective serotonin reuptake inhibitors which were developed based on the monoamine theory, where other food and drug administration (FDA)-approved antidepressants are based on the monoamine theory. Recent studies reported that rubrofusarin inhibits monoamine oxidase-A, which can degrade norepinephrine, serotonin, and dopamine, with good blood–brain barrier penetration value [23]. These suggest that rubrofusarin may increase monoamine neurotransmitter levels in the brain and demonstrate antidepressant-like effects. This study aimed to test the effects of rubrofusarin on the onset of depressive symptoms in a chronic restraint stress-induced depression-like model and mode of action

Results
Chronic Rubrofusarin Administration Blocked CRS-Induced Synaptic Dysfunctions
Discussion
Animals
Restraint Stress
Objective Recognition Memory Test
Forced Swimming Test
Tissue Slices Preparation
Floro-Jade B Staining
Immunohistochemistry
Hippocampal Slices Preparation and Electrophysiology
Microinfusion of Drugs
4.10. Statistics
Full Text
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