Hippocampal microRNA-26a-3p deficit contributes to neuroinflammation and behavioral disorders via p38 MAPK signaling pathway in rats

Abstract

Background Neuronal injury is considered a critical risk factor in the pathogenesis of most neurological and neuropsychiatric diseases. However, the underlying molecular mechanisms and identification of potential therapeutic targets for preventing neuronal injury associated with brain function remain largely uncharacterized. Therefore, identifying neural mechanisms would put new insights into the progression of this condition and provide novel therapeutic strategies for the treatment of these diseases. Methods Stereotactic injection of AAV virus was used to knock-down the miR-26a-3p within hippocampus of rats. Behavioral changes was detected by open field test (OFT), elevated plus maze (EPM), forced swim test (FST) and sucrose preference test (SPT). The inflammatory cytokines and related proteins were verified by real-time quantitative PCR, immunoblotting or immunofluorescence assay. Golgi staining and electron microscopy analysis was used to observe the dendritic spine, synapse and ultrastructural pathology. SB203580 (0.5 mg/kg) were administered daily to prevent p38 MAPK via an intraperitoneal (i.p.) injection. Finally, electrophysiological method was used to examine the synaptic transmission via whole-cell patch-clamp recording. Results Here, we showed that miR-26a-3p deficiency within hippocampal regions leads to the activation of microglia, increased level of pro-inflammatory cytokines and behavioral disorders in rats, effects which appear to be mediated by directly targeting the p38 mitogen-activated protein kinase (MAPK)–NF-κB signaling pathway. Specifically, we found that the enhanced glia-activation may consequently result in neuronal deterioration that mainly presented as the dysregulation of structural and functional plasticity in hippocampal neurons. In contrast, preventing p38 pathway by SB203580 significantly ameliorated abnormal behavioral phenotypes and neuronal jury resulting from miR-26a-3p knock-down. Conclusion These results suggest that the normal expression of miR-26a-3p exerts neuroprotective effects via suppressing neural abnormality and maintaining neuroplasticity to against behavioral disorders in rats. These effects appear to involve a down-regulation of p38 MAPK-NF-κB signaling within the hippocampal region. Taken together, these findings provide evidence that miR-26a-3p can function as a critical factor in regulating neural activity and suggest that the maintaining of normal structure and function of neurons might be a potential therapeutic strategy in the treatment of neurological disorders. Graphical Abstract

Bone mesenchymal stem cell-derived exosomal miR-26a-3p promotes autophagy to attenuate LPS-induced apoptosis and inflammation in pulmonary microvascular endothelial cells

“…In addition, studies have indicated that miR-26a-3p can enhance autophagosome/lysosomal activity, facilitate synaptic plasticity, and repress neuronal cell apoptosis [13]. Moreover, miR-26a-3p absence results in an elevation in the expressions of pro-inflammatory factors IL-6β, IL-4, and TNF-α in the injured neurons [14]. Our results discovered that miR-26a-3p expression in BMSCs was reduced via the exosome inhibitor GW4869.…”

“…MiR-26a-3p is closely related to synaptic formation and plasticity in the nervous system. The involvement and modulation of miR-26a-3p have been found in neurological diseases and some cancers [13,14,32]. In addition, studies have indicated that miR-26a-3p can enhance autophagosome/lysosomal activity, facilitate synaptic plasticity, and repress neuronal cell apoptosis [13].…”

“…MiR-26a-3p has been confirmed to be expressed in the brains and is associated with neuropsychiatric disorders [13]. Wang et al [14] suggest miR-26a-3p depletion is conducive to inflammation in hippocampus by regulating p38 MAPK pathway. In addition, miR-26a-3p can regulate the malignant development of several cancers [15].…”

Chlorogenic Acid Alleviates Chronic Stress-Induced Intestinal Damage by Inhibiting the P38MAPK/NF-κB Pathway

“…ERK and JNK were unchanged after chronic stress or CGA treatment. p38MAPK is an important member of MAPK, which is not only involved in the cell cycle, development, differentiation, cell death, senescence, and tumorigenesis, but also acts as a specific serine/threonine kinase to regulate inflammation. , A large number of studies have shown that p38 could activate the NF-κB signaling pathway, thereby causing inflammation in some diseases such as IBD, alcohol-induced hepatic injury, lung inflammation, and Parkinson’s. − After SB203580 intervention, the phosphorylation level of p65 was significantly reduced, and the transcription and translation levels of TNF were significantly reduced. The intestinal damage was also significantly reduced.…”

Comprehensive analysis of N6-methyladenosine-related RNA methylation in the mouse hippocampus after acquired hearing loss

“…As a prominent intracellular signaling pathway, the MAPK pathway is of great importance in several critical physiological processes, including learning, memory, development, and cell differentiation [ 37 , 38 ]. The MAPK cascade is required for spatial and contextual learning in mice and is associated with hippocampal neurodegeneration [ 39 , 40 ]. It is noteworthy that Notch signaling pathways exhibited a correlation with both hyper- and hypomethylation of distinct genes (Fig.…”