Microvasculature, the Trigeminal System and Migraine

Aims of this thesis In Part I the focus is on experimental models of migraine, that are applied in pharmacological as well as in pathophysiological studies. Calcitonin gene-related peptide is the key neuropeptide in migraine pathophysiology. CGRP is being extensively researched, especially as a novel anti-migraine drug target. In Chapter 3 we review existing experimental models that can be applied to study the effects of the novel CGRP receptor antagonists and the recently developed antibodies directed against CGRP and its receptor. In Chapter 4 we comment on an existing experimental model to demonstrate its limitations with regard to distinguishing between structures important to migraine, like the intracranial part of the middle meningeal artery. In Chapter 5 we describe our experimental trigeminal nerve-mediated vasodilatation model. We developed this model to study trigeminovascular pathophysiological and pharmacological mechanisms of migraine. In Chapter 6 we investigate the effects of the anti-migraine drug sumatriptan with this model, to validate it as a biomarker for studies on future anti-migraine drugs. Besides its direct burden, migraine has recently also been identified as a major independent risk factor for cardiovascular disease. Yet, cross-sectional studies investigating the vascular dysfunction in migraine patients have reported conflicting results. This may relate to the fact that the experimental models used to identify vascular dysfunction were diverse and often limited. Therefore, in Chapter 7 we compared different measures of vascular function to assess their reproducibility and their usefulness to identify endothelial dysfunction. In Chapter 8 we applied one of these measures, the post-occlusive reactive hyperemia (PORH), to characterize the microvascular function in a knock-in mouse (V235fs KI mice) model of migraine. In Part II we evaluate the role of female sex hormones in migraine. The prevalence of migraine is much higher in women than in men. Hormonal milestones in women are

Trigeminovascular effects of propranolol in men and women, role for sex steroids

OBJECTIVE: Assess whether propranolol modulates the trigeminovascular system in both men and women. METHODS: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T (max)) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double‐blind, placebo‐controlled cross‐over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old). RESULTS: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin‐induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. INTERPRETATION: Propranolol (80 mg) inhibits capsaicin‐induced increases in dermal blood flow in a sex‐dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system

Migraine and perimenopause

Perimenopause and migraine are closely linked. The hormonal instability during the perimenopausal period not only causes vasomotor symptoms and mood disturbances, but also increases migraine incidence. Women do report new onset migraine during this period, but the increased incidence is reported by women with menstrually related migraine (MRM). The hormonal fluctuations can be stabilized with hormone replacement therapy (HRT), while simultaneously improving the migraine in some patients. The increased stroke risk in women with migraine with aura (MA) should be taken into consideration when intending to treat perimenopausal women with migraine with HRT

Pain perception in women with menstrually-related migraine

Background: Cyclic hormonal fluctuations influence migraine incidence and severity. Previously, we described reduced menstrual cyclicity in estradiol levels and dermal blood flow reaction to capsaicin in female migraineurs. It is unclear whether pain perception in women with migraine is influenced by the menstrual cycle. Methods: Women with menstrually-related migraine (n = 14), healthy age-matched controls (n = 10) and postmenopausal women (n = 15) were asked to grade trigeminal and non-trigeminal painful stimuli on a numeric pain rating scale on menstrual cycle day 19–21 (mid-luteal) and day 1–2 (early follicular). Results: In women with menstrually-related migraine, trigeminal pain remained low throughout the cycle. Controls showed increased trigeminal pain during the mid-luteal phase compared to the early follicular phase. Changes throughout the cycle were significantly different between women with MRM and controls. Conclusion: The compromised menstrual cyclicity of pain perception in women with menstrually-related migraine parallels our earlier findings on estradiol levels and dermal blood flow

Vascular Risk Score and Associations With Past, Current, or Future Migraine in Women: Cohort Study

Background and ObjectivesMigraine has consistently been associated with an increased risk of cardiovascular disease (CVD) events. It remains, however, unclear to what extent cardiovascular risk profiles might be linked with migraine activity status and how these profiles relate to the development of migraine.MethodsWe used data from a cohort study of female health professionals (Women's Health Study, n = 27,539, age ≥45 years at baseline) without a history of CVD or other major diseases and who provided a blood sample at baseline. Framingham risk scores (FRSs) estimating the 10-year risk of coronary heart disease calculated at baseline were used to create vascular risk categories. The presence or development of self-reported migraine was assessed by questionnaires. Women were classified as having no migraine, history of migraine (experienced migraine in the past but did not experience any migraine attacks in the year before enrollment), active migraine at baseline (active), or incident migraine (first report of migraine during follow-up but not at baseline). We used multinomial logistic regression models to calculate ORs for the association between FRS categories and migraine status.ResultsOf the 27,539 participants, a total of 21,927 women did not report migraine, 1,500 women reported a history of migraine, 3,579 had migraine at baseline, and 533 reported migraine for the first time during follow-up. The odds of the probability of having a history of migraine at baseline (vs never migraine) was 76% higher among those with FRS ≥10% compared with FRS ≤1% after adjustment (OR = 1.76, 95% CI 1.39-2.23). In contrast, having FRS ≥10% was associated with reduced odds of having active migraine at baseline (OR = 0.64, 95% CI 0.52-0.80) and with newly reported migraine during follow-up (OR = 0.42, 95% CI 0.22-0.81) when compared with women with FRS category ≤1% and those not reporting migraine. A similar association pattern was observed for FRS categories 5%-9% and 2%-4%.DiscussionHigh FRS categories were only observed among women with a history of migraine but not with active migraine at baseline or incident migraine after baseline. Our results suggest that the life course of migraine should be considered when studying associations with the vascular system. Our data further suggest that a relatively healthy vascular system, as assessed by the FRS, is associated with active migraine status or developing migraine in the future

The influence of migraine and female hormones on capsaicin-induced dermal blood flow

Background Migraine is much more common in females than in males, and occurrence is associated with changes in female sex hormones. Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and variations in female sex hormones may affect CGRP sensitivity and/or production. Objectives Investigate repeatability, gender differences, influence of the menstrual cycle and of migraine on CGRP-dependent changes in dermal blood flow (DBF). Methods CGRP-dependent increases in DBF were assessed using laser Doppler perfusion imaging after topical application of 300 or 1000 µg capsaicin on the forearm of healthy subjects and migraine patients. Results In healthy males, DBF response did not vary over time and was comparable with DBF in male migraineurs. In healthy females, capsaicin-induced DBF responses to both doses of capsaicin were higher during menstruation compared to the late-secretory phase (p < 0.05); this menstrual cycle dependence was absent in female migraine patients. Compared to healthy subjects, female migraineurs displayed a higher DBF response both during menstruation and during the late-secretory phase (p < 0.05). Conclusions An increased capsaicin-induced, CGRP-mediated DBF response was observed during menstruation in healthy women, but in female migraine patients this increased response was not affected by the menstrual cycle.status: publishe

Angiotensin II Type 2 Receptor– and Acetylcholine-Mediated Relaxation

Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y-) from the Y chromosome, allowing XY- mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY-Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY-Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY- female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors

Survival outcome of tonsillar squamous cell carcinoma (TSCC) in the context of human papillomavirus (HPV) : a systematic review and meta-analysis

Objective: The objective of our study was to assess whether HPV-positive TSCC had better survival and prognosis rates, when compared to HPV-negative TSCC. Method: A systematic review and meta-analysis was performed comparing HPV status in TSCC patients. TSCC was confirmed with histopathology and HPV status was confirmed with PCR, immunohistochemistry and/or in-situ-hybridisation. The primary endpoints were overall survival (OS) and disease free survival (DFS). Results: Twenty-four studies were identified, involving 1921 TSCC cases, of which 56.2% (1079) were HPV positive. OS was significantly higher in patients with HPV-positive compared to HPV-negative TSCC in years 1e5 (OR 2.54, P < 0.01; OR 2.93 P < 0.01; OR 2.74 P < 0.01; OR 2.20 P < 0.01, and OR 2.14 P < 0.01 respectively). Similarly, DFS was also significantly higher in patients with HPV-positive compared to HPV-negative TSCC in years 1e3 (OR 2.86, P < 0.01; OR 2.60 P < 0.02; and OR 2.60 P < 0.01 respectively), which was attenuated in years 4 and 5 (OR 1.83, P = 0.10 and OR 1.50, P = 0.12). Conclusion: This is the largest meta-analysis with 1921 patients, comparing non-HPV induced TSCC and HPV induced TSCC, looking at outcome and survival. HPV-positive had better OS and DFS