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.

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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.

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