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.
Background and objectivesBased on the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study, neurological disorders are a major cause of morbidity and mortality worldwide. However, there has been no comprehensive assessment of neurological disorders in Asia. Data from the GBD 1990-2019 study were investigated to provide new details for neurological disorders in Asia.MethodsThe burden of common neurological disorders in Asia was calculated for 1990 and 2019 as incidence, prevalence, deaths, and disability-adjusted life-years (DALYs). 13 common neurological disorders were analyzed. Data are presented as totals and by sex, age, year, location, risk factors and socio-demographic index (SDI) and shown as counts and rates.ResultsIn 2019, the most burdensome neurological disorders in Asia with respect to the absolute number of DALYs were stroke (98.8 million [95% UI, 91.0∼107.0]), migraine (24.6 million [95% UI, 3.4∼56.4]), Alzheimer’s disease (AD) and other dementias (13.5 million [95% UI, 5.9∼29.8]). From 1990 to 2019, the absolute number of DALYs and deaths caused by combined neurological disorders (deaths by 60.7% and DALYs by 17.6%) increased, but the age-standardised rates (deaths by 34.1% and DALYs by 36.3%) decreased. The burden of neurological disorders peaked among individuals aged 65-74 years and was higher among males than among females; moreover, this burden varied considerably across Asian subregions and countries. Risk-attributable DALYs accounted for 86.9%, 28.5%, and 11.1% of DALYs for stroke, AD and other dementias and multiple sclerosis (MS), respectively. For communicable neurological disorders, the crude rates of all metrics were moderately to strongly negatively correlated with the SDI, while the crude rate of stroke prevalence was moderately positively correlated with the SDI.ConclusionNeurological disorders were the leading cause of DALYs and the second leading cause of deaths in Asia in 2019, and the burden may likely increase with the growth and aging of the Asian population. Urgent measures are needed for prevention, treatment, rehabilitation, and support services for common neurological disorders regionally and nationally.
Previous clinical and basic studies have shown that migraine is associated with cognitive impairment, anxiety, and depression. It severely affects the quality of life. In this study, C57BL/6 mice were randomly divided into four groups: IS group, IS+M group, and IS+S group with repeated application of dural inflammatory soup (IS) stimulation to establish a migraine model, followed by PBS, memantine, and sumatriptan interventions, respectively; the blank control group underwent the same treatment procedure but with PBS instead of IS and intervention drugs. The cognitive function of the mice was used as the main outcome indicator. After application of the IS, mice showed reduced pain threshold for mechanical stimulation, decreased learning memory capacity, attention deficit, a reduced number of dendritic spines in hippocampal neurons, and altered synaptic ultrastructure. The cognitive function indexes of mice in the IS+M group recovered with changes in Arc protein expression to a level not statistically different from that of the Control group, while the IS and IS+S groups remained at lower levels. The present results suggest that Arc-mediated synaptic plasticity may be an essential mechanism of cognitive dysfunction in migraine.
BackgroundTargeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine.MethodsWe used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation.ResultsIn the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia.ConclusionThe migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.
In this paper, we, four students with diverse social locations, explore the development of preservice educators’ professional identities as political resisters. Through our experiences in an Ontario college, we found commonality in our emerging need to resist “alarming discourses” (Whitty et al., 2020, p. 8). By dissecting and analyzing the neoliberal narrative perpetuated by our educational institution, we refused the notion of being the good ECE (Langford, 2007). Rejecting the universalism and totalism of Western European curricular and pedagogical inheritances, we set out to create a space to embrace alternative narratives to critically question our role and the expectations of our profession in a neoliberal world. This space was used for ECEC advocacy and brought together our student community, creating an opportunity to mentor while fostering human connections from our stories. Through collaboration, we reaffirm the importance of building community and reciprocal mentorship for nurturing and developing political agency within our field. We are motivated to sustain this critical space, to serve as a place of resistance for other students who question “universal truths.” Education comes from more than the diploma received. Keywords: Early childhood educators, professional identity, resistance, student advocacy, post-secondary institutions, ethics of care
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