ω-3 DPA Protected Neurons from Neuroinflammation by Balancing Microglia M1/M2 Polarizations through Inhibiting NF-κB/MAPK p38 Signaling and Activating Neuron-BDNF-PI3K/AKT Pathways

Abstract

Microglia M1 phenotype causes HPA axis hyperactivity, neurotransmitter dysfunction, and production of proinflammatory mediators and oxidants, which may contribute to the etiology of depression and neurodegenerative diseases. Eicosapentaenoic acid (EPA) may counteract neuroinflammation by increasing n-3 docosapentaenoic acid (DPA). However, the cellular and molecular mechanisms of DPA, as well as whether it can exert antineuroinflammatory and neuroprotective effects, are unknown. The present study first evaluated DPA’s antineuroinflammatory effects in lipopolysaccharide (LPS)-activated BV2 microglia. The results showed that 50 μM DPA significantly decreased BV2 cell viability after 100 ng/mL LPS stimulation, which was associated with significant downregulation of microglia M1 phenotype markers and proinflammatory cytokines but upregulation of M2 markers and anti-inflammatory cytokine. Then, DPA inhibited the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 pathways, which results were similar to the effects of NF-κB inhibitor, a positive control. Second, BV2 cell supernatant was cultured with differentiated SH-SY5Y neurons. The results showed that the supernatant from LPS-activated BV2 cells significantly decreased SH-SY5Y cell viability and brain-derived neurotrophic factor (BDNF), TrkB, p-AKT, and PI3K expression, which were significantly reversed by DPA pretreatment. Furthermore, DPA neuroprotection was abrogated by BDNF-SiRNA. Therefore, n-3 DPA may protect neurons from neuroinflammation-induced damage by balancing microglia M1 and M2 polarizations, inhibiting microglia-NF-κB and MAPK p38 while activating neuron-BDNF/TrkB-PI3K/AKT pathways.

Epigallocatechin Gallate Protects against Hypoxia-Induced Inflammation in Microglia via NF-κB Suppression and Nrf-2/HO-1 Activation

“…Hypoxia leads to M1 microglia, an activated phenotype of macrophage-like cell, which mainly produces pro-inflammatory mediators including TNF-α, IL-1β, and IL-6 and triggers ROS production, possibly inducing a cascade of events leading to neuronal damage [ 26 , 27 ]. Alternatively, M2 microglia facilitate recovery via promoting the release of anti-inflammatory cytokines, such as IL-10 and TGF-β after brain injury [ 28 , 29 , 30 ]. Therefore, eliminating pro-inflammatory mediators in the neuro-inflammatory response under hypoxic conditions is an important strategy for developing inflammation-related disease therapy.…”

Tooth Loss Suppresses Hippocampal Neurogenesis and Leads to Cognitive Dysfunction in Juvenile Sprague–Dawley Rats

“…The intracellular region of TrkB has intrinsic tyrosine kinase activity. After binding with TrkB, BDNF activates the intracellular region, resulting in enhanced self-phosphorylation of TrkB, which leads to promote the survival of nerve cells and increase synaptic plasticity and neurogenesis ( Xiang et al, 2014 ; Peng et al, 2020 ; Liu et al, 2021 ; Wang et al, 2022 ). Increasing the synaptic plasticity can affect long-term potentiation and enhance the learning process and memory formation.…”

Anti-Inflammatory Function of Plant-Derived Bioactive Peptides: A Review

“…Inflammatory signaling pathways are complicated network structures with complex interactions among targets, and therefore, the simultaneous consideration of multiple pathways is required. The PI3K/Akt pathway, a crossover pathway of multiple signaling pathways, can regulate both the MAPK and NF-κB pathways that indirectly inhibit inflammation [ 28 ]. Akt protein phosphorylation can act on the ERK of the MAPK pathways, and the p38 and IKKβ of the NF-κB pathway.…”