Search Results (29)

Background/Objectives: Migraine is associated with neurogenic inflammation, trigeminovascular activation, oxidative stress, and systemic metabolic changes. However, circulating antioxidant-related biomarkers in older adults with migraine remain insufficiently characterized. We examined whether self-reported migraine history was associated with serum uric acid (UA), albumin, and total protein levels in the Swedish Adoption/Twin Study of Aging (SATSA), including exploratory analyses in migraine-discordant twin pairs. Methods: This cross-sectional analysis used the first in-person testing wave of SATSA. Participants aged ≥50 years with complete migraine status and biomarker data were included. Serum UA was the primary outcome; albumin and total protein were secondary outcomes. Group differences were assessed using t-tests, Wilcoxon rank-sum tests, or chi-square tests, as appropriate. Linear regression models were adjusted for age, sex, and body mass index. Paired analyses were conducted in 13 migraine-discordant twin pairs. Results: Among 411 participants, 23 reported a migraine history. Participants with migraine had lower serum UA (4.39 vs. 5.15 mg/dL, p = 0.011), albumin (4.40 vs. 4.55 g/dL, p = 0.019), and total protein (7.16 vs. 7.43 g/dL, p = 0.008). These associations remained significant after adjustment. In discordant twin pairs, UA was lower in twins with migraine than in co-twins without migraine (4.34 vs. 4.72 mg/dL, p = 0.050), whereas albumin and total protein differences were not significant. Conclusions: Self-reported migraine history in older adults was associated with lower circulating UA, albumin, and total protein levels. These exploratory, cross-sectional findings should be interpreted as associative rather than causal and require confirmation in longitudinal studies. Full article

Migraine is a complex neurovascular disorder with a multifactorial pathophysiology involving genetic, metabolic, and environmental factors. Increasing evidence indicates that oxidative stress plays a key role in the development of migraine; however, it is unclear whether oxidative imbalance acts primarily as a causal factor or occurs as a consequence of migraine-related processes. Oxidative stress, defined as an imbalance between reactive oxygen species production and antioxidant defense mechanisms, contributes to neuronal hyperexcitability, mitochondrial dysfunction, and neuroinflammation—key mechanisms underlying migraine pathogenesis. Studies have shown elevated markers of oxidative damage and altered antioxidant enzyme activity in migraine patients. Simultaneously, metabolic and inflammatory changes associated with migraine may further exacerbate oxidative imbalance, suggesting a bidirectional relationship. Furthermore, genetic factors such as SOD2, GPX1, and CAT significantly influence susceptibility to oxidative stress and migraine. The CALCA gene, encoding CGRP, links oxidative stress mechanisms with neurogenic inflammation and activation of the trigeminovascular system. This article reviews the current evidence regarding the role of oxidative stress in migraine and discusses its relationship to molecular and genetic mechanisms. Particular attention is given to genes involved in oxidative pathways, mitochondrial function, and inflammatory responses, which may help explain individual susceptibility and variability in clinical presentation. Full article

Migraine severely impacts the quality of life of young adults. During the past few years, many studies have been done regarding the pathophysiology of this condition. There has been intense debate regarding CGRP, but research is still underway about the glymphatic system and PACAP. This review provides an overview of the current literature in this area of migraine pathophysiology. The inflammatory mediators and neuropeptides that activate trigeminovascular pathways can be accumulated during migraine attacks as a result of a failure of glymphatic clearance. Neuroinflammation, CGRP, CSD, and sleep have all been linked to the glymphatic system and migraine. In this article, we also discuss the latest hypotheses regarding the PACAP pathway in the neurophysiology of migraine. Additionally, recent research suggests that glymphatic dysfunction could enhance PACAP-mediated signaling. This article will explore possible correlations between these mechanisms and migraine pathophysiology. Full article

Migraine is a highly prevalent and disabling neurovascular disorder that represents a major global health burden due to its significant impact on quality of life and socioeconomic costs. Increasing evidence suggests that migraine pathophysiology involves complex interactions between neuronal hyperexcitability, vascular dysregulation, oxidative stress, and neuroinflammatory processes. Oxidative and nitrosative stress are increasingly recognized as key contributors to migraine mechanisms, influencing mitochondrial dysfunction, cortical spreading depression, and trigeminovascular activation. Nitric oxide plays a central role in these processes by regulating vascular tone, nociceptive signaling, and neurogenic inflammation through downstream pathways such as the soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling cascade. Dysregulation of nitric oxide signaling and increased oxidative stress may contribute to endothelial dysfunction and impaired cerebrovascular regulation observed in migraine patients. In addition, accumulating evidence highlights the role of neuroinflammatory mechanisms, including microglial activation and cytokine-mediated signaling, which may amplify nociceptive transmission within trigeminal pathways. Migraine is increasingly recognized as a systemic disorder associated with several comorbid conditions, including Parkinson’s disease, fibromyalgia, and autoimmune diseases such as Sjögren’s syndrome. This review summarizes recent advances regarding the interactions between oxidative stress, nitric oxide signaling, endothelial dysfunction, and neuroinflammation in migraine and discusses their potential therapeutic implications. Full article

Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances. The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology. Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization. Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders. Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions. Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy. Full article

Background and Objectives: Migraine is the most common primary headache disorder worldwide, negatively affecting quality of life and limiting the functionality of individuals. Although its pathogenesis is not fully understood, it is known that activation of the trigeminovascular system, neurogenic inflammation, and oxidative stress are among the main components of migraine. In this context, we aimed to investigate the possible role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway, which plays a key role in the regulation of cellular oxidative stress, in the development of chronic diseases such as migraine. Materials and Methods: In this study, the oxidative stress parameters total oxidant level (TOS), total antioxidant level (TAS), and oxidative stress index (OSI) and changes in the Nrf2/Keap1 signaling pathway were analyzed in migraine patients. Results: The results showed that Keap1 levels were significantly higher in migraine patients compared with the control group, whereas the Nrf2 and TAS levels were low. In addition, increased levels of oxidized LDL (oxLDL) and glycogen synthase kinase-3 beta (GSK3B), which are oxidative stress markers, confirmed that the oxidative stress burden was high in migraine patients. The fact that OSI values were significantly higher in migraine patients clearly demonstrates that systemic oxidative stress was out of balance in these individuals. Conclusions: In conclusion, this study reveals that oxidative stress and the Nrf2/Keap1 signaling pathway play an important role in the pathogenesis of migraine. Decreased Nrf2 activity and increased Keap1 levels suggest that the antioxidant defense system is insufficient in migraine patients. These findings suggest that the Nrf2/Keap1 signaling pathway may be considered as a potential target for migraine treatment and that the development of new treatment strategies to reduce oxidative stress may be beneficial. Full article

Magnesium is an essential mineral involved in hundreds of biochemical reactions, with particular relevance to maintaining neural homeostasis, modulating neurotransmitter systems, and regulating inflammatory and oxidative stress mechanisms. This comprehensive review aims to evaluate the potential role of magnesium in the pathophysiology and treatment of three prevalent neurological and psychiatric disorders—depression, migraine, and Alzheimer’s disease—as well as its broader implications for cognitive health. Current research suggests that magnesium deficiency is associated with the development of depression, as magnesium influences glutamatergic and GABAergic neurotransmission, as well as the activity of the hypothalamic–pituitary–adrenal (HPA) axis, both of which play critical roles in stress responses and mood regulation. Additionally, magnesium’s anti-inflammatory properties may contribute to the alleviation of depressive symptoms. In the context of migraine’s pathophysiology, magnesium plays a role in regulating cerebral vascular tone, modulating the trigeminovascular system, and reducing neuronal hyperexcitability, which may explain the observed correlation between magnesium levels and the incidence of migraines. Regarding Alzheimer’s disease, preclinical and epidemiological studies suggest that magnesium may contribute to modulating neurodegenerative processes and preserving cognitive function; however, due to the heterogeneity of the current findings, further longitudinal and interventional studies are necessary to determine its precise clinical relevance. This review aims to enhance the understanding of the relationship between magnesium and these disorders through a narrative review of relevant clinical studies. The findings may provide insights into the potential therapeutic applications of magnesium and guide the future directions of the research into the prevention and treatment of depression, migraine, and Alzheimer’s disease and overall cognitive health. Full article

Introduction: Migraine is a prevalent neurological disorder characterized by recurrent headaches with autonomic and neurological symptoms, significantly impacting quality of life globally. Its pathogenesis involves genetic, neurological, inflammatory, and metabolic factors, with insulin resistance and metabolic dysfunction increasingly recognized as important contributors. Historically, it has been known that certain foods can trigger migraine attacks, which led for many years to the recommendation of elimination diets—now understood to primarily target histamine-rich foods. Over the past two decades, attention has shifted toward underlying metabolic disturbances, leading to the development of dietary approaches specifically aimed at addressing these dysfunctions. Methods: A scoping literature review was conducted using PubMed and Embase to evaluate the relationships among migraine, insulin-related mechanisms, neurogenic inflammation, and dietary interventions. Initial searches focused on “MIGRAINE AND (neurogenic inflammation)” (2019–15 April 2025), followed by expanded searches from 1950 onward using terms such as “MIGRAINE AND (insulin, insulin resistance, hyperinsulinism)”, and “MIGRAINE AND (diet, dietary, nutrition, nutritional)”. A specific search also targeted “(INSULIN OR insulin resistance OR hyperinsulinism) AND (neurogenic inflammation)”. Abstracts were screened, full texts were retrieved, and duplicates or irrelevant publications were excluded. No filters were applied by article type or language. Systematic reviews and meta-analyses were prioritized when available. Results: Migraine pathogenesis involves trigeminovascular system activation, neurogenic inflammation mediated by CGRP and PACAP, immune dysregulation, mast cell activation, and cortical spreading depression (CSD). Emerging evidence highlights significant associations between migraine, insulin resistance, and hyperinsulinism. Hyperinsulinism contributes to migraine through TRPV1 sensitization, increased CGRP release, oxidative stress, mitochondrial dysfunction, and systemic inflammation. Metabolic dysfunction, including obesity and insulin resistance, exacerbates migraine severity and frequency. Dietary interventions, particularly anti-inflammatory, Mediterranean, and ketogenic diets, show promise in reducing migraine frequency and severity through mechanisms involving reduced inflammation, oxidative stress, improved mitochondrial function, and glucose metabolism stabilization. Conclusions: The interplay between insulin resistance, metabolic dysfunction, and neuroinflammation is crucial in migraine pathophysiology. Targeted dietary interventions, including ketogenic and Mediterranean diets, demonstrate significant potential in managing migraines, emphasizing the need for personalized nutritional strategies to optimize therapeutic outcomes. Full article

Background/Objectives: Migraine is a disease that stands out for its high prevalence and socioeconomic costs. It involves the entire trigeminovascular system, the signaling substances, and their targets. However, the role of meningeal mast cells in migraine is still unclear. To better understand one of the components of neurogenic inflammation underlying migraine pathophysiology, we developed an in vivo rat model in which the dura mater was exposed bilaterally to investigate the influence of topiramate on capsaicin-induced mast cell degranulation and CGRP release from dura mater. Methods: On the day of the experiment, rats were anesthetized, and a craniectomy was performed on each parietal bone. Test substances were applied in situ over the dura mater using the right and left sides of the dura mater for the test and control, respectively. After exposure, the dura mater was processed for mast cell staining and counting. Using this setup, the effect of capsaicin (10⁻³ M) was evaluated in rats of both sexes, and subsequently the effect of in situ (10⁻³ M, 20 µL) and (20 mg/kg/day for 10 days) topiramate treatment on mast cell degranulation and CGRP release were evaluated. Results: In both female and male rats, there was a greater amount of degranulated mast cells in the side stimulated by capsaicin compared to the control side in both females (18 ± 3% vs. 74 ± 3%; p = 0.016) and males (28 ± 2% vs. 74 ± 3%, p = 0.016). In the group treated with topiramate for 10 days prior to the experiments, capsaicin did not induce mast cell degranulation (control 20 ± 1% vs. capsaicin 22 ± 1%, p = 0.375) in contrast to animals treated for 10 days with gavage control (control 25 ± 1% vs. capsaicin 76 ± 1%, p = 0.016). Topiramate applied in situ concomitant with capsaicin did not protect the mast cells from degranulation in response to capsaicin (38 ± 2% vs. 44 ± 1%, p = 0.016). There was a significant reduction in CGRP release from the dura mater in the group treated with topiramate for 10 days compared to the control. Conclusions: This study demonstrates a novel experimental model wherein systemic administration of topiramate is observed to modulate the impact of capsaicin on meningeal mast cell degranulation. Full article

Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is known about the effects of SAH on these neurons in preclinical models. The present study evaluated changes in CGRP levels and expression in trigeminal primary afferents innervating the dura mater 72 h after experimentally induced SAH in adult rats. SAH, eliciting marked damage revealed by neurological examination, significantly reduced the density of CGRP-immunoreactive nerve fibers both in the dura mater and the trigeminal caudal nucleus in the medulla but did not affect the total dural nerve fiber density. SAH attenuated ex vivo dural CGRP release by ~40% and in the trigeminal ganglion, reduced both CGRP mRNA levels and the number of highly CGRP-immunoreactive cell bodies. In summary, we provide novel complementary evidence that SAH negatively affects the integrity of the CGRP-expressing rat trigeminal neurons. Reduced CGRP levels suggest likely impaired meningeal neurovascular functions contributing to SAH complications. Further studies are to be performed to reveal the importance of impaired CGRP synthesis and its consequences in central sensory processing. Full article

Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation. Dysfunction of ion channels could result in neuronal excitability and peripheral or central sensitization. This narrative review covers the current understanding of the biological mechanisms leading to activation and sensitization of the trigeminovascular pain pathway, with a focus on recent findings on ion channel activation and modulation. Furthermore, we focus on the kynurenine pathway since this system contains kynurenic acid, which is an endogenous glutamate receptor antagonist substance, and it has a role in migraine pathophysiology. Full article

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine. Full article

Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, activates the trigeminovascular system. In the present study, we investigated CGRP mRNA expression in TG neurons in a CSD-based mouse migraine model. Our in situ hybridization analysis showed that CGRP mRNA expression was observed in smaller-sized neuronal populations. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral TG. However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger in the 48 h and 72 h post-CSD groups than in the control group. The proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters less than 14 μm became significantly less at several time points after CSD. In contrast, we found significantly greater proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters of 14–18 μm at 24 h, 48, and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift in CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy. Full article

Background: Multiple studies have suggested that paralgesia (hyperalgesia and cutaneous allodynia) in migraine reflects the activation and sensitisation of the trigeminovascular system (TGVS). In particular, it reflects the second-order and higher nerve centre sensitisation, which is caused and maintained by neuroinflammation. Microglia activation leads to the release of proinflammatory cytokines involved in inflammatory responses. Accumulating evidence indicates that electroacupuncture (EA) is effective in ameliorating paralgesia, but the underlying mechanisms of EA in migraine attacks caused by microglia and microglia-mediated inflammatory responses are still unclear. The purpose of this study was to explore whether EA could ameliorate the dysregulation of pain sensation by suppressing microglial activation and the resulting neuroinflammatory response, and to evaluate whether this response was regulated by Toll-like receptor 4 (TLR4)/nuclear factor-kappa B(NF-κB) in the trigeminal nucleus caudalis (TNC) in a rat model of migraine. Methods: Repeated Inflammatory Soup (IS) was infused into the dura for seven sessions to establish a recurrent migraine-like rat model, and EA treatment was administered at Fengchi (GB20) and Yanglingquan (GB34) after daily IS infusion. Facial mechanical withdrawal thresholds were measured to evaluate the change in pain perception, and plasma samples and the TNC tissues of rats were collected to examine the changes in calcitonin gene-related peptide (CGRP), the Ibal-1-labelled microglial activation, and the resulting inflammatory response, including interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and their regulatory molecules TLR4/NF-κB, via enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and Western blot analysis. Results: Repeated IS injections into the dura induced facial mechanical paralgesia, which is the manifestation of migraine attacks, and increased the expression of CGRP, Ibal-1, microglial mediated inflammatory cytokines (IL-1β, TNF-α, IL-6), and regulatory molecules TLR4/NF-κB. EA at GB20/34 significantly attenuated repetitive IS-induced pain hypersensitivity. This effect was consistent with decreased levels of CGRP and inflammatory cytokines in the plasma and the TNC via the inhibition of microglia activation, and this response may be regulated by TLR4/NF-κB. Conclusions: EA ameliorated paralgesia in repetitive IS-induced migraine-like rats, which was mainly mediated by a reduction in microglial activation and microglial-mediated inflammatory responses that could be regulated by TLR4/NF-κB. Full article

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered. Full article