Aerobic exercise reverses the NF-κB/NLRP3 inflammasome/5-HT pathway by upregulating irisin to alleviate post-stroke depression

Abstract

Background: Post-stroke depression (PSD) is one of the most common and serious sequelae of stroke.The pathogenesis of PSD involves both psychosocial and biological mechanisms, and aerobic exercise is a potential therapeutic target. We conducted an in-depth exploration of the protective mechanisms of aerobic exercise in a PSD mouse model. Methods:In this study, C57BL/6 mice were used as the research objects, and a PSD mouse model was established by combining middle cerebral artery occlusion and chronic unpredictable mild stimulation.Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, adeno-associated virus microinjection technology, co-immunoprecipitation, fluorescence in-situ hybridization, and western blotting were performed. A moderate-load treadmill exercise was used for aerobic exercise intervention. The moderate-intensity aerobic exercise training method adopted 0 slopes and treadmill adaptation training for 5 days. We verified the effects of aerobic exercise on the nuclear factor kappa B (NF-κB)/nucleotide-binding oligomerization domain--like receptor protein 3 (NLRP3) inflammasome/5-hydroxytryptamine (5-HT) pathway.Results: Aerobic exercise effectively alleviated the neurological damage caused by PSD (P<0.01). The results from the PSD mouse model in vivo were consistent with those of the cell experiments. Moreover, overexpression of irisin improves depression-like behavior in PSD mice. We confirmed that aerobic exercise is involved in PSD through 5-HT, which inhibits NF-κB/NLRP3 inflammasome initiation through irisin and alleviates mitochondrial damage under stress by reducing calcium overload, thereby inhibiting NLRP3 inflammasome activation.Conclusions: Aerobic exercise reversed the NF-κB/NLRP3 inflammasome/5-HT pathway by upregulating irisin expression to alleviate PSD.

Effect of Shenqi Jieyu formula on inflammatory response pathway in hippocampus of postpartum depression rats

“…5-HT, as well as 5-HT(1A), inhibits apoptotic cell death, and increases intranuclear levels of the p50 and p65 subunits of NF-κB [ 61 ]. 5-HT, when increased by aerobic exercise, can reduce inflammasome activation and alleviate stress induced mitochondrial damage by decreasing calcium overload through the way inhibiting NF-κB/NLRP3 inflammasome initiation [ 62 ] 5-HT secretion has been shown to significantly elevate NF-κB signaling during hypoxia in gut enterochromaffin cells [ 63 ]. In addition, 5-HT1AR inhibitor can decrease levels of TNF-α, GFAP and Iba1 in the hippocampus and inhibit phospho-NF-κB in the hippocampus of Aβ1-42-injected mice [ 64 ].…”

Aerobic Exercise Improves Depressive-like Behavior in CUMS-Induced Rats via the SIRT3/ROS/NLRP3 Signaling Pathway

“…Exercise, as a non-pharmacological treatment method, has been widely studied for its anti-inflammatory effects [ 44 ]. Exercise can inhibit inflammatory responses and promote anti-inflammatory responses through various pathways, and multiple signaling pathways are involved in regulating anti-inflammatory effects, such as NF-κB and JAK/STAT [ 45 , 46 ]. NF-κB is a transcription factor that is widely regarded as the main regulator of inflammatory responses.…”

A New Perspective on Hippocampal Synaptic Plasticity and Post-stroke Depression

“…The neurotransmitter 5-HT is involved in depression In the hippocampus, 5-HT acts as a neurotransmitter and is involved in regulating synaptic plasticity and neurogenesis (Micheli et al 2018b;Palacios-Filardo and Mellor 2019). Aerobic exercise can improve depression-like behavior in PSD by upregulating 5-HT levels (Tang et al 2022). Another study also found that both diosgenin and agomelatine exert their antidepressant effects by increasing 5-HT levels in the hippocampus of rats (Daszuta et al 2005;Yang et al 2017).…”