Depression is a serious medical illness that is one of the most prevalent psychiatric disorders. Corticosterone (CORT) increases depression-like behavior, with some effects on anxiety-like behavior. 2-Phenethylamine (PEA) is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Here, we show that PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway in CORT-induced depression. To investigate the potential effects of PEA on CORT-induced depression, we first treated CORT (50 μM)-induced hippocampal neurons with 100 μM PEA for 24 h. We found that treatment with CORT altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. Next, we used a mouse model of CORT-induced depression. Mice were treated with CORT (20 mg/kg) for 21 days, followed by assessments of a battery of depression-like behaviors. During the final four days of CORT exposure, the mice were treated with PEA (50 mg/kg). We found that CORT injection promoted depression-like behavior and significantly decreased BDNF and TrkB expression in the hippocampus. However, treatment with PEA significantly ameliorated the behavioral and biochemical changes induced by CORT. Our findings reveal that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in a mouse model of CORT-induced depression.

Perfluorinated compounds (PFCs), organofluoride compounds comprising carbon-fluorine and carbon-carbon bonds, are used as water and oil repellents in textiles and pharmaceutical tablets; however, they are associated with potential neurotoxic effects. Moreover, the impact of PFCs on neuronal survival, activity, and regulation within the brain remains unclear. Additionally, the mechanisms through which PFCs induce neuronal toxicity are not well-understood because of the paucity of data. This study elucidates that perfluorooctanoic acid (PFOA) and perfluoroheptanoic acid (PFHpA) exert differential effects on the survival and activity of primary cortical neurons. Although PFOA triggers apoptosis in cortical neurons, PFHpA does not exhibit this effect. Instead, PFHpA modifies dendritic spine morphogenesis and synapse formation in primary cortical neuronal cultures, additionally enhancing neural activity and synaptic transmission. This research uncovers a novel mechanism through which PFCs (PFHpA and PFOA) cause distinct alterations in dendritic spine morphogenesis and synaptic activity, shedding light on the molecular basis for the atypical behaviors noted following PFC exposure. Understanding the distinct effects of PFHpA and PFOA could guide regulatory policies on PFC usage and inform clinical approaches to mitigate their neurotoxic effects, especially in vulnerable population.

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, induces neuroinflammation. However, present understanding regarding its fundamental role in neuroinflammation remains limited. Therefore, in this study, we aimed to clarify the potential association between PFOA and astrocyte activation via the modulation of the endoplasmic reticulum (ER) stress-autophagy axis. The results obtained revealed that PFOA activated astroglia in A-172 astrocytoma cells and primary astrocytes by upregulating the expression levels of autophagy-related proteins (ATG5, BECN1, SQSTM1, and MAP1LC3B-II). It also activated autophagy in A-172 astrocytoma cells and primary astrocytes via the upstream activation of ER stress-related proteins, such as ATF4, GRP78, and CHOP. Further, the pharmacological inhibition of ER stress as well as autophagy prevented PFOA-induced activation of astrogliosis in PFOA-treated A-172 cells and primary astrocytes. We also observed that PFOA-mediated activation of GFAP upregulated the transcription of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6. These findings confirmed the existence of a relationship between ER stress-induced autophagy and astrogliosis in PFOA-treated astrocytes, suggesting that targeting the ER stress-autophagy axis may be a potential therapeutic strategy for reducing PFOA-induced neuroinflammation.