Approximately 1.5 million Americans over the age of 40 suffer from vision-threatening age-related macular degeneration (AMD), a number expected to rise with aging demographics. AMD exists in two defined forms: dry (non-exudative) which accounts for up to 90% of cases, and wet (exudative). Dry AMD is characterized by the slow buildup of drusen under the retina, eventually leading to geographical atrophy. Wet AMD involves vascular endothelial growth factor (VEGF)-induced blood vessel formation from the choriocapillaris into the subretinal space, a process referred to as neovascularization. These newly formed blood vessels leak fluid into the subretinal space leading to atrophy of the retinal pigment epithelium (RPE) and associated photoreceptors. Despite clinical distinctions, dry and wet AMD share overlapping pathophysiological features, marked by degeneration of the RPE and the overlying photoreceptors. A major feature of the RPE and photoreceptors are their high metabolically activity and their large numbers of mitochondria, which generate reactive oxygen species (ROS) during ATP production. ROS-induced oxidative stress damages lipids, proteins and DNA, resulting in cellular degradation which contributes to AMD. Because of the elevated oxidative stress levels, antioxidants which neutralize ROS are often recommended as a treatment for AMD. A major objective of this review is to examine the role of melatonin, a powerful and multifunctional antioxidant, in altering the trajectory of AMD progression. Melatonin is synthesized in the RPE and photoreceptors of young individuals but its expression declines with age. As shown in an epidemiological report, its loss contributes to age-related degeneration of the RPE and photoreceptors. Moreover, melatonin inhibits VEGF, suggesting that it would be useful as a treatment for wet AMD. This review explores melatonin-mediated protective mechanisms in the retina, a likely mechanistic basis for the already published findings showing that melatonin use by humans is associated with delayed AMD, and potential clinical applications.

Calcitonin gene-related peptide (CGRP), encoded by the CALCA gene, plays a central role in migraine pathophysiology; however, it remains unclear whether migraine is associated with persistent systemic molecular alterations affecting the CGRP pathway during the interictal phase. Transient receptor potential cation channel subfamily A member 1 (TRPA1) stimulates the release of CGRP from nerve endings. We investigated gene-specific and global epigenetic regulatory mechanisms associated with CALCA and TRPA1 expression in the peripheral blood of 56 patients with episodic migraine in the interictal phase and 36 headache-free controls. Expression of CALCA, TRPA1, and genes encoding epigenetic regulators, histone deacetylases 1 and 6 (HDAC1 and HDAC6), was assessed by quantitative real-time PCR. DNA methylation of CALCA and TRPA1 was evaluated using methylation-specific PCR. Expression of other epigenetic regulators miRNA-375, miRNA-382, and miRNA-34a was determined using TaqMan MicroRNA assays. No significant differences were observed between migraine patients and controls in CALCA or TRPA1 expression, nor in DNA methylation of these genes. Similarly, no differences were found in the expression of miRNA-375 and miRNA-382. In contrast, miRNA-34a expression was significantly reduced in migraine patients. Moreover, the expression of HDAC1 and HDAC6 was significantly decreased in migraine. Despite the established role of CGRP in migraine, no evidence of persistent systemic dysregulation of CALCA or TRPA1 was detected in peripheral blood during the interictal phase. However, altered expression of miRNA-34a, HDAC1, and HDAC6 suggests the presence of broader epigenetic and post-transcriptional regulatory disturbances. These findings support a model in which migraine is associated with dysregulation of regulatory mechanisms rather than stable alterations of individual target genes.

Cellular senescence, a state where cells permanently exit the cycle but remain metabolically active, plays a role in cardiovascular diseases (CVD), including heart failure (HF). Senescent cells accumulate in aging and stressed heart tissue, releasing pro-inflammatory cytokines, chemokines, and enzymes that affect endothelial cells. This ongoing inflammation exacerbates cardiac damage, induces endothelial dysfunction, and triggers secondary senescence across various cardiac cell types. Senescent cardiomyocytes contribute to reduced systolic function by causing mitochondrial damage, impaired contractility, and metabolic dysfunction, leading to lower cardiac output and symptoms such as fatigue and exercise intolerance in HF patients. Additionally, inflammation from senescent endothelial cells and loss of microvasculature impair coronary blood flow and oxygen delivery, worsening symptoms such as shortness of breath, angina-like discomfort, and fluid retention by disrupting cardiac energy metabolism and increasing filling pressures. A key factor linking cellular senescence with HF is sirtuin 1 (SIRT1), a histone deacetylase with antioxidant activity. SIRT1 acts as a hormetic regulator in the heart, being beneficial within a narrow range but potentially harmful when overstimulated. As drugs targeting senescence are emerging to treat CVD, it is important to evaluate how SIRT1 may influence the connection between senescence and HF to improve anti-senescent therapies. In this narrative/perspective review, we explore the molecular mechanisms underlying senescence in HF development and how SIRT1 might modulate these processes for therapeutic benefit.

Malocclusion arises from complex interactions among genetic, environmental, and developmental factors. While genetic contributions are well established, epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and RNA chemical modifications, have emerged as plausible regulators of craniofacial growth and dentoalveolar remodeling. This structured narrative review critically evaluates current evidence on the role of epigenetic regulation in the development of malocclusion and in orthodontic tooth movement. Most available data derive from in vitro studies, animal models, and investigations of related craniofacial processes rather than from direct analyses of defined malocclusion phenotypes in humans. Consequently, the evidence base is largely indirect and heterogeneous. To address this limitation, we applied a qualitative appraisal framework that considered study design, methodological rigor, and the directness of the evidence. Experimental findings indicate that epigenetic mechanisms are dynamically regulated by mechanical forces and may influence osteogenesis, chondrogenesis, periodontal remodeling, and individual variability in orthodontic response. However, robust causal studies directly linking specific epigenetic modifications to malocclusion phenotypes remain lacking. Although biological plausibility is strong, a substantial gap persists between mechanistic insights and clinical translation. At present, the clinical utility of epigenetic markers in orthodontic diagnosis, treatment strategy, or prognosis remains limited. Future research should prioritize well-designed longitudinal human studies integrating epigenetic profiling with clearly defined malocclusion phenotypes to establish causal relationships and enable clinically relevant applications.

The delivery of therapeutic nucleic acids to target cells faces many challenges, and novel carriers continue to be investigated. Metallodendrimers present several beneficial features as drugs and nucleic acid carriers, including specificity toward pathological cells, low toxicity to normal cells, and the capacity to cross cellular membranes. In the present work, we investigated the efficacy of synthesized Cu(II) metallodendrimers in delivering pro-apoptotic siRNAs, specifically siBCL2 and siMCL1, to human liver carcinoma HepG2 cells. The resulting siRNA/dendrimer complexes exhibited a strong pro-apoptotic effect, characterized by increased levels of reactive oxygen species, mitochondrial membrane depolarization, and activation of caspases 3 and 7. Quantitatively, second-generation Cu(II) dendriplexes reduced HepG2 cell viability to approximately 40% of control (siBcl-2/CCD NO-2), downregulated BCL2 and MCL1 mRNA by up to 3.5- and 4.9-fold respectively, increased the combined early- and late-apoptotic populations from <5% in untreated cells to 43% (siBcl-2/CCD NO-2), and inhibited HepG2 migration almost completely, ≤15% of wound closure for second generation dendriplexes, while sparing peripheral blood mononuclear cells. These findings highlight the potential of the siRNA/Cu dendrimers to inhibit cancer cell invasion and metastasis, which is critical for effective cancer therapy, making them a promising tool in the treatment of human hepatocellular carcinoma and other cancers.

Migraine may signal early signs of aging-related processes, such as reduced autophagy, increased reactive oxygen and nitrogen species (RONS), and low-grade inflammation in people prone to migraine, without necessarily indicating systemic aging. While migraine is not an age-related condition, brain aging might be accelerated by cellular senescence in neurons and glia, contributing to cognitive decline in migraine patients. Although neurons are postmitotic cells, they can undergo postmitotic cellular senescence, which may contribute to the chronicity of migraine. Oxidative stress is a key factor inducing senescence and also plays a role in migraine development, as the brains of migraine sufferers show an over-reliance on mitochondria that produce an excess of RONS. These RONS can lower the threshold for cortical spreading depression and directly activate trigeminovascular nociceptors through RONS-sensitive ion channels, resulting in calcitonin gene-related peptide-dependent migraine pain. Excessive RONS can also damage DNA, and abnormal repair of single-strand DNA breaks caused by migraine-related brain activity may connect migraine with senescence. Defects in autophagy could activate cellular senescence and stabilize senescence-associated secretory phenotype. Impaired autophagy in microglia might trigger secretory autophagy and the release of brain-derived nuclear factor, which could induce autophagy in neurons to eliminate cellular debris caused by oxidative stress. This sequence of events is possible but has not yet been demonstrated in material from migraine patients and animal models. Cellular senescence may influence migraine through various mechanisms, including oxidative stress, cortical spreading depression, abnormal DNA damage responses, and impaired autophagy. Currently, there is no direct evidence linking cellular senescence to migraine, but it is unclear whether such research has been conducted to date, and we have argued that these studies are warranted.

Chronic migraine (CM) is the ultimate and most burdensome form of the transformation from episodic migraine (EM), called chronification. The mechanism behind migraine chronification is poorly known and difficult to explore as CM has the same spectrum of pathogenesis as EM and the EM-CM transition is bidirectional. Central sensitization (CS) is a key phenomenon in migraine: its mechanisms include disturbed neural plasticity, which is the ability of the nervous system to adapt to endo- and exogenous changes. Cutaneous allodynia, a maker of central sensitization, may be an easy-to-determine marker of the EM-CM transition. Pituitary adenylate cyclase-activating peptide, a pro-inflammatory, vasodilatory and pain-producing neuropeptide, which has been proposed as an alternative to CGRP target in migraine, was shown to improve CS by regulating synaptic plasticity in the trigeminal nucleus caudalis in CM rats. Oxytocin and its receptor were found to influence CS through modulating synaptic plasticity in CM mice. Similar results were obtained for ephrin type-B receptor and its ligands. These and other studies suggest that neural plasticity may be important in CM pathogenesis. Still, its involvement in migraine chronification requires further studies which should include patients/animals with EM and CM. In this narrative/hypothesis paper, we review the current literature on the molecular mechanisms of CM pathogenesis and try to link them with neural plasticity and central sensitization to support the hypothesis that it is a key element in migraine chronification.

Although periodontal disease (PD) is reported to be associated with changes in various genes and proteins in both invading bacteria and the host, its molecular mechanism of pathogenesis remains unclear. Changes in immune and inflammatory genes play a significant role in PD pathogenesis. Some reports relate alterations in cellular epigenetic patterns to PD characteristics, while several high-throughput analyses indicate thousands of differentially methylated genes in both PD patients and controls. Furthermore, changes in DNA methylation patterns in inflammation-related genes have been linked to the efficacy of periodontal therapy, as demonstrated by findings related to the cytochrome C oxidase II gene. Distinct DNA methylation patterns in mesenchymal stem cells from PD patients and controls persisted despite the reversal of phenotypic PD. Methyl groups for DNA methylation are supplied by S-adenosylmethionine, which is synthesized with the involvement of folate, an essential nutrient known to play a role in maintaining mitochondrial homeostasis, reported to be compromised in PD. Folate may benefit PD through its antioxidant action against reactive oxygen and nitrogen species that are overproduced by dysfunctional mitochondria. As such, DNA methylation, dietary folate, and mitochondrial quality control may interact in PD pathogenesis. In this narrative/hypothesis review, we demonstrate how PD is associated with changes in mitochondrial homeostasis, which may, in turn, be improved by folate, potentially altering the epigenetic patterns of immune and inflammatory genes in both the nucleus and mitochondria. Therefore, a folate-based dietary intervention is recommended for PD prevention and as an adjunct therapy. At the same time, further research is needed on the involvement of epigenetic mechanisms in the beneficial effects of folate on PD studies.

The increasing prevalence of age-related macular degeneration (AMD), a disease that can result in the loss of central vision, is an emerging problem worldwide due to aging societies. Growing patient numbers create a challenge for the healthcare system. Understanding the mechanisms of AMD pathogenesis will aid in early, personalized, and efficient intervention, helping to mitigate this issue. Current diagnostic methods rely on optical coherence tomography and angiography imaging, which identify existing damages, but do not provide information on the mechanisms behind them. In the present work, we demonstrate a difference in the serum RNA profile between neovascular AMD (nAMD) patients and controls. Moreover, the RNA profile of nAMD patients corresponded with anatomical changes in the retinal fluid compartments as well as atrophic changes of the retina. We followed two independent ways to control false positive leads, and when these approaches were combined, thioredoxin-related transmembrane protein 4 (TMX4) was observed to be differentially expressed by both approaches. This finding opens a new pathway in AMD studies, which are limited due to restricted access to live human target material and the limited value of animal models of human AMD.

The prevalence of stroke in patients with migraine is higher than in the general population, suggesting certain shared mechanisms of pathogenesis. Migrainous infarction is a pronounced example of the migraine–stroke connection. Some cases of migraine with aura may be misdiagnosed as stroke, with subsequent mistreatment. Therefore, it is important to identify these shared mechanisms of pathogenesis contributing to the migraine–stroke connection to improve diagnosis and treatment. Sirtuins (SIRTs) are a seven-member family of NAD+-dependent histone deacetylases that can epigenetically regulate gene expression. Sirtuins possess antioxidant properties, making them a first-line defense against oxidative stress, which is important in the pathogenesis of migraine and stroke. Mitochondrial localization of SIRT2, SIRT3, and SIRT4 supports this function, as most reactive oxygen and nitrogen species are produced in mitochondria. In this narrative review, we present arguments that sirtuins may link migraine with stroke through their involvement in antioxidant defense, mitochondrial quality control, neuroinflammation, and autophagy. We also indicate mediators of this involvement that can be, along with sirtuins, therapeutic targets to ameliorate migraine and prevent stroke.

Epigenetic studies in migraine provided results on the occurrence or lack of epigenetic modifications of genes whose products are important in migraine pathogenesis. However, these studies focus on single genes without analyzing how epigenetic modifications can affect complex signaling pathways. This narrative/hypothesis review aims to provide information on how the reactive oxygen and nitrogen species (RONS)-transient receptor potential cation channel subfamily A member 1 (TRPA1)-calcitonin gene-related peptide (CGRP) axis functions, suggesting that its epigenetic modifications could be a significant factor in migraine pathophysiology. Oxidative stress is both a cause and a consequence of migraine, and reactive oxygen and nitrogen species (RONS), like other noxious stimuli, may activate the transient receptor potential cation channel subfamily A member 1 (TRPA1) to send pain signals. Methylation of the TRPA1 gene correlates with various pain states; however, the results of these studies are largely inconsistent. DNA methylation and the action of non-coding RNAs are important in the alternative RNA processing of the calcitonin-related polypeptide alpha (CALCA) gene and its transcript to produce calcitonin gene-related peptide (CGRP). The release of CGRP and substance P from trigeminal neuron terminals, mediated by TRPA1 activation and involving mitogen-activated protein kinase 1/2, is a primary mechanism driving migraine headaches. Epigenetic memory may be related to neural plasticity and migraine chronification. Therefore, the RONS-TRPA1-CGRP signaling pathways may be important in migraine pathogenesis, as demonstrated in experimental animals by the phenomenon of cortical spreading depolarization. The RONS-TRPA1-CGRP axis plays a significant role in the pathogenesis of migraine and other pain-related syndromes. Epigenetic modifications of the genes encoding the components of the antioxidant defense system, TRPA1 and CGRP, are crucial in migraine pathogenesis, prevention, and therapy. However, due to the sequence specificity of the axis, only non-coding RNAs can currently be considered for therapeutic intervention in migraine, targeting the epigenetic profile of the RONS-TRPA1-CGRP axis.

Tryptophan (TRP) metabolism produces various neuroactive substances in the gastrointestinal tract, as well as in the central and peripheral nervous systems and intestinal microbiota. Initially centered on the serotonin pathway in TRP metabolism and TRP itself, many studies are now focusing on the kynurenine pathway, with an increasing interest in the indole pathway. Several TRP metabolites have been associated with migraines, suggesting that TRP metabolism may serve as a potential therapeutic target. However, these studies have significant limitations, including a small number of participants, a lack of standardized diets prior to and/or during clinical trials, and insufficient information regarding the transformation of TRP after its intake. Furthermore, no thorough study encompasses all the essential components of TRP metabolism: products, enzymes, receptors, and transporters. Different mechanisms may explain the involvement of TRP metabolism in migraines, including glutamate signaling and neurovasodilatory, immune, oxidative, and inflammatory processes. The results of studies on the role of TRP metabolism in migraine may be helpful for making dietary recommendations for migraine prevention and clinical management; however, individual characteristics for metabolizing TRP should be considered. The aim of this narrative perspective review is to critically present the results of studies on the role of TRP metabolism in migraine and explore their implications for migraine prevention and therapy. Unlike many other reviews that focus solely on either the serotonin or kynurenine pathway, our paper addresses all three primary TRP metabolism pathways.

Migraine prevalence in females is up to 3 times higher than in males and females show higher frequency, longer duration, and increased severity of headache attacks, but the reason for that difference is not known. This narrative review presents the main aspects of sex dimorphism in migraine prevalence and discusses the role of sex-related differences in mitochondrial homeostasis in that dimorphism. The gender dimension is also shortly addressed. The imbalance between energy production and demand in the brain susceptible to migraine is an important element of migraine pathogenesis. Mitochondria are the main energy source in the brain and mitochondrial impairment is reported in both migraine patients and animal models of human migraine. However, it is not known whether the observed changes are consequences of primary disturbance of mitochondrial homeostasis or are secondary to the migraine-affected hyperexcitable brain. Sex hormones regulate mitochondrial homeostasis, and several reports suggest that the female hormones may act protectively against mitochondrial impairment, contributing to more effective energy production in females, which may be utilized in the mechanisms responsible for migraine progression. Migraine is characterized by several comorbidities that are characterized by sex dimorphism in their prevalence and impairments in mitochondrial functions. Mitochondria may play a major role in sexual dimorphism in migraine through the involvement in energy production, the dependence on sex hormones, and the involvement in sex-dependent comorbidities. Studies on the role of mitochondria in sex dimorphism in migraine may contribute to precise personal therapeutic strategies.

Age-related macular degeneration (AMD) is an eye disease that can lead to legal blindness and vision loss. In its advanced stages, it is classified into dry and neovascular AMD. In neovascular AMD, the formation of new blood vessels disrupts the structure of the retina and induces an inflammatory response. Treatment for neovascular AMD involves antibodies and fusion proteins targeting vascular endothelial growth factor A (VEGFA) and its receptors to inhibit neovascularization and slow vision loss. However, a fraction of patients with neovascular AMD do not respond to therapy. Many of these patients exhibit a subretinal fibrotic scar. Thus, retinal fibrosis may contribute to resistance against anti-VEGFA therapy and the cause of irreversible vision loss in neovascular AMD patients. Retinal pigment epithelium cells, choroidal fibroblasts, and retinal glial cells are crucial in the development of the fibrotic scar as they can undergo a mesenchymal transition mediated by transforming growth factor beta and other molecules, leading to their transdifferentiation into myofibroblasts, which are key players in subretinal fibrosis. Autophagy, a process that removes cellular debris and contributes to the pathogenesis of AMD, regardless of its type, may be stimulated by epithelial–mesenchymal transition and later inhibited. The mesenchymal transition of retinal cells and the dysfunction of the extracellular matrix—the two main aspects of fibrotic scar formation—are associated with impaired autophagy. Nonetheless, the causal relationship between autophagy and subretinal fibrosis remains unknown. This narrative/perspective review presents information on neovascular AMD, subretinal fibrosis, and autophagy, arguing that impaired autophagy may be significant for fibrosis-related resistance to anti-VEGFA therapy in neovascular AMD.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Yet, its treatment has serious challenges and is unsuccessful in a considerable fraction of patients. One reason may be a limited understanding of the molecular mechanisms underlying AF. Recent studies suggest that oxidative stress is involved in AF pathogenesis. Enhanced oxidative stress is largely determined by disrupted mitochondrial homeostasis, as cardiomyocytes heavily rely on mitochondrial energy production and calcium transfer between mitochondria and the sarcoplasmic reticulum. Atrial fibrillation involves metabolic, structural, and electrical remodeling, all of which are influenced by mitochondrial mechanisms. Mitochondrial homeostasis is controlled by mitochondrial quality control (mtQC), which is a multi-pathway mechanism to maintain integrity and functionality of mitochondria. Impaired mtQC may result in disturbed mitochondria-related calcium handling, decreased energy production, mitochondria-related inflammation and fibrosis, and impaired mitophagy. Sirtuins (SIRTs) are a family of seven members of histone deacetylases which have antioxidant properties, and three of them are localized to mitochondria. Therefore, at least some SIRTs may ameliorate enhanced oxidative stress related to damaged mitochondria. SIRTs have shown potential to improve AF outcomes in studies on AF patients and animal models. Therefore, SIRTs may have potential to ameliorate AF by decreasing oxidative stress and restoring mitochondrial homeostasis disrupted in AF. In this narrative review, we provide information on how mitochondrial dysfunctions, expressed as a disturbance in mtQC, contribute to AF through oxidative stress, calcium handling abnormalities, energy deficiency, inflammation and fibrosis, and genetic changes. In addition, we present the protective potential of sirtuins in AF.

Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a crucial triad involved in HF pathogenesis, interconnected by oxidative stress. Identifying a common pathway involving these three components could be valuable in developing new treatment strategies. Since HF is the end result of several cardiovascular diseases, this review highlights the main HF precursors and explores the roles of mitochondrial quality control (mtQC), autophagy, and sirtuins in HF development. Dysfunctional mitochondria may play a key role by enhancing oxidative stress and influencing autophagy and sirtuins, both of which possess antioxidant properties. The dual nature of autophagy—its pro-life and pro-death roles—may contribute to different outcomes in HF related to oxidative stress. As mtQC, autophagy, and sirtuins may interact, we present data on their mutual dependencies in HF. However, the specificity of these interactions remains unclear and needs further investigation, which could help identify new therapeutic targets. In conclusion, the interplay between mtQC, autophagy, and sirtuins may be crucial in HF pathogenesis and could be leveraged in developing HF treatments.

Background: The mixed type of irritable bowel syndrome (IBS-M) is characterized by recurrent constipation and diarrhea. The cause of the variability of these symptoms is not sufficiently understood. The aim of this study was to perform metagenomic and metabolic assessment of the gut microbiome in constipation and diarrheal period of IBS-M. Methods: This study included 30 women, aged 28–47 years old, with the symptoms which aligned with those of IBS-M, according to the Rome IV Criteria. Results: In both periods of the disease, the dysbiosis index (DI), the Shannon diversity index (SDI), the hydrogen–methane and ammonia breath tests, as well as the selected bacterial metabolites (-p-hydroxyphenyl acetic acid (HPA), 3-indoxyl sulfate (Indican, 3-IS)), and hippuric acid (A) in urine, were determined. The dysbiosis index (DI) in the period of constipation was 3.73 ± 0.90 points, and in the diarrheal period it did not change significantly 3.93 ± 0.75 points (p > 0.05). During the diarrheal period, the diversity of bacteria increases from 2.16 ± 0.59 to 2.74 ± 0.50 points on the Shannon dietary index (p < 0.001). The gut microbiome profile also changed, especially during the diarrheal period where an abundance of Bifidobacterium spp. and Lactobacillus spp. decreased significantly. In addition, during this period, the levels of hydrogen and ammonia in breath air increased, while the methane level decreased. The differences also concern the results of urinary metabolites, especially related to hippuric acid and indican. During the diarrheal period, the levels of hydrogen and ammonia ions increased, while the methane level decreased. The differences also concern the results of urinary metabolites, especially related to hippuric acid and indican. Conclusions: In patients with IBS-M, periodic changes in the profile and metabolism of the gut microbiome occur, which coexist with recurrent symptoms such as constipation and diarrhea.

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1–2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.