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P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine.

ABSTRACT: Migraine is the second most common form of headache disorder and the second leading cause of disability worldwide. Cognitive symptoms ranked second resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved in hyperalgesia in migraine. However, the role of P2X7R in migraine-related cognitive impairment is still ill-defined. The aim of this study was to explore the molecular mechanisms underlying migraine-related cognitive impairment and the role of P2X7R in it. Here we used a well-established mouse model of migraine that triggered migraine attacks by application of inflammatory soup (IS) to the dura. Our results showed that repeated dural IS stimulation triggered upregulation of P2X7R, activation of NLRP3 inflammasome, release of proinflammatory cytokines (IL-1β and IL-18) and activation of pyroptotic cell death pathway. Gliosis (microgliosis and astrogliosis), neuronal loss and cognitive impairment also occurred in the IS-induced migraine model. No significant apoptosis or whiter matter damage was observed following IS-induced migraine attacks. These pathological changes occurred mainly in the cerebral cortex and to a less extent in the hippocampus, all of which can be prevented by pretreatment with a specific P2X7R antagonist Brilliant Blue G (BBG). Moreover, BBG can alleviate cognitive impairment following dural IS stimulation. These results identified P2X7R as a key contributor to migraine-related cognitive impairment and may represent a potential therapeutic target for mitigating cognitive impairment in migraine.

SUBMITTER: Wang Y

PROVIDER: S-EPMC9250730 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeNeuroinflammation is an essential causative factor in the pathogenesis and progression of cognitive impairment. The present study aims to evaluate the critical role of microRNA-138-5p (miR-138-5p) in hippocampal neuroinflammation and cognitive impairment through the NLRP3/caspase-1 signaling pathway in rats.Material and methodsWe established the cognitive impairment rat model and RM (Rat microglia) microglial cellular inflammation model by intracerebroventricular (icv) injection or stimulation of lipopolysaccharide (LPS). Morris water maze (MWM) and Y-maze tests were performed to assess the cognitive behaviors. Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme-linked immune-sorbent assay (ELISA) and Western blot analysis were utilized to evaluate mRNA or protein expression. Bioinformatic analysis and dual-luciferase reporter gene assay were performed to verify the targeting relationship between NLRP3 and miR-138-5p. Besides, Hematoxylin and eosin (H&E) staining and immunohistochemistry were applied to observe the neuronal morphology and detect the positive cells of the hippocampus, respectively.ResultsCompared to the control groups, LPS-treated rats exhibited significantly impaired learning and memory in MWM and Y-maze tests. The expression of NLRP3, caspase-1 and pro-inflammation cytokines (IL-1β and IL-18) were upregulated, while miR-138-5p was downregulated both in rat hippocampus and RM cells treated with LPS. MiR-138-5p is downregulated in microarray data of cognitive impairment animals and could directly target the 3'-UTR of NLRP3. Furthermore, upregulation of miR-138-5p improved impaired cognitive functions, while inhibited hippocampal neuroinflammation demonstrated by decreased expression of NLRP3/caspase-1 axis, pro-inflammation cytokines and microglial activation. This study demonstrates for the first time that miR-138-5p suppresses the hippocampal NLRP3/caspase-1 signaling pathway activation in cognition impaired rats.ConclusionThe low expression of miR-138-5p after LPS administration may contribute to the activation of the NLRP3/caspase-1 pathway, leading to hippocampal neuroinflammation and cognitive impairment in rat models. These findings indicate a promising therapeutic avenue for cognitive disorders.

Project description:BackgroundNeuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer's disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD.MethodsSixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers.ResultsAdministration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS.ConclusionsColitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Project description:BackgroundPrevious studies revealed inconsistent results regarding association between migraine and cognitive impairment. In addition, previous studies found inconsistent results regarding the association between migraine and risk of dementia. Thus, the study aimed to make a meta-analysis exploring comparison result in different types of cognitive function between migraine patients and non-migraine subjects. In addition, meta-analysis was made to explore the association between migraine and risk of dementia.MethodsArticles published before June 2022 were searched in the following databases: PubMed, Web of Science, SCOPUS, EMBASE, EBSCO, PROQUEST, ScienceDirect and Cochrane Database of Systematic Reviews. Results were computed using STATA 12.0 software.ResultsMeta-analysis showed lower general cognitive function and language function in migraine group, compared to no migraine group (general cognitive function: standard mean difference (SMD) = - 0.40, 95% CI = - 0.66 to - 0.15; language: SMD = - 0.14, 95% confidence interval (CI) = - 0.27 to - 0.00), whereas the study showed no significant difference in visuospatial function, attention, executive function and memory between migraine group and no migraine group (visuospatial function: SMD = - 0.23, 95% CI = - 0.53 to 0.08; attention: SMD = - 0.01, 95% CI = - 0.10 to 0.08; executive function: SMD = - 0.05, 95% CI = - 0.16 to 0.05; memory: SMD = - 0.14, 95% CI = - 0.30 to 0.03). In addition, the meta-analysis showed a significant association between migraine and risk of dementia (odds ratio (OR)/relative risk (RR) = 1.30, 95% CI = 1.11 to 1.52).ConclusionsIn conclusion, the meta-analysis demonstrated lower general cognitive function and language function in migraine. In addition, migraine is associated with an increased risk of all-cause dementia, VaD and AD. These results suggest a significant association between migraine and cognitive impairment. Because of the association between migraine and cognitive impairment, neurological physician should be vigilant and effectively intervene in migraineurs with high risk factors of cognitive impairment to prevent the development of cognitive impairment.

Project description:Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

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P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine.

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