Elevated Frequency of HLA Shared-Haplotypes in Migraine Families

SYNOPSIS
Associations between HLA antigens and disease susceptibility have been investigated in several pathological conditions. Previous studies in selected migraine populations did not reveal any association with the HLA system. It is widely accepted that migraine is a disease with familial incidence. The genetic basis of migraine occurrence within 8 families with more than one member affected in two generations was studied. 60 individuals were studied; 33 of them were affected by migraine. HLA-A,B,C,DR typing was performed in 41 individuals using the microlymphocytotoxicity technique of Terasaki.
The studied pedigrees failed to identify a particular HLA antigen or HLA haplotype as a genetic marker of migraine. Among the total number of HLA typed individuals entering the study, Sib-pair analysis was done in 20 pairs. The observed frequency of shared-haplotypes differed from the expected frequency: 60% of compared pairs shared one haplotype (expected frequency 50%) and 30% shared two haplotypes (expected frequency 25%).     

TNFA gene: the -308 promoter polymorphism in migraine

Molecular analysis of TNFA alleles in Italian subjects affected by migraine was performed in order to define the involfement of HLA region genes in migraine. No statistically significant differences in TNFA allele distribution between patients and controls were observed.     

Primary Headache and Helicobacter Pylori

H. pylori infection has recently been associated with various vascular disorders. The aim of this study was to investigate its role in primary headache, a pathology strictly associated with vascular alterations. A total of 200 subjects affected by primary headache were evaluated. H. pylori infection was diagnosed by the 13C urea breath test. Headache was classified in tension-type headache, cluster headache, and migraine with or without aura. Prevalence of H. pylori infection and gastrointestinal (GI) symptoms were evaluated. H. pylori infection was found in 40% of the patients; prevalence of migraine without aura was found to be significantly greater in infected patients. The positive group showed no significant differences in the prevalence of the GI symptoms evaluated. In 30 infected patients, it was assessed whether the eradication of the bacterium was able to reduce frequency, intensity, and duration of clinical attacks of headache. After eradication, clinical attacks of headache completely disappeared in 17% of patients. Moreover, intensity, duration, and frequency of headache attacks were reduced in 69% of the remaining subjects. In conclusion, H. pylori infection is common in primary headache; bacterium eradication appears to be related to a significant reduction in clinical attacks of the disease.     

Relationship Between HLA System in Cluster Headache and Clinical Response to Lithium Therapy

SYNOPSIS
The relationship between the major system of histocompatibility antigens and cluster headache has already been studied by our group, and decreased frequency of HLA-B14 antigen shown in cluster headache patients in comparison to a control population.
The therapy of cluster headache with lithium salts is already widely acclaimed; nevertheless there are patients who derive no benefit or must suspend treatment due to side-effects. Thus we wanted to study the relationship between genetic markers of patients with the illness and the therapeutic efficacy of lithium salts.
35 episodic cluster headaches have been studied; they had been already typed for the HLA antigens. The patients were treated with lithium carbonate for a period of 3 months. As parameters for evaluation of the efficacy of treatment, the headache index ratio, the wake-sleep rhythm and the pupil diameter measurement were studied.
Statistical evaluation was made and it was possible to separate two subgroups of patients: "responders" and "non responders" to lithium therapy. The phenotypical frequencies in the two subgroups was analyzed using the X² test.
A higher frequency of HLA-B18 antigen (23.8% vs 0%; p< 0.0005; pc<0.06) and of HLA-A9 antigen (42.9% vs 14.3%) showed in the "responders" group. In the "non responders" group was found a higher frequency in HLA-A1 antigen (35.7% vs 14.3%).     

A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects

Background and Purpose

The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.

Experimental Approach

Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were synthesized and characterized in various enzymatic assays. The effects of O-7460 on high-fat diet intake were tested in mice.

Key Results

Of the new compounds, O-7460 exhibited the highest potency (IC₅₀ = 690 nM) against the human recombinant DAGLα, and selectivity (IC₅₀ > 10 μM) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off-target’, that is, the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB₁ or CB₂ cannabinoid receptors (K_i > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 μM) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0–12 mg·kg⁻¹, i.p.) inhibited the intake of a high-fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.

Conclusions and Implications

O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Beneficial effects of Helicobacter pylori eradication on migraine: a 12-month follow-up study

Helicobacter pylori (H. pylori) has been recently associated with some organic and functional vascular disorders. In particular, our group found a high prevalence of H. pylori in patients affected by migraine and a significant improvement of migraine symptoms after eradication of the bacterium, during a follow-up period of 6 months. However, seasonal variations may affect clinical manifestations of migraine, thus influencing our previous results. The present study evaluated the effect of H. pylori eradication during a 1-year follow-up period in a population of 148 consecutively enrolled migraine patients. H. pylori infection was assessed by ¹³C-urea breath test. Infected subjects underwent specific antibiotic treatment in order to eradiate the bactrium. Frequency, intensity and duration of attacks of migraine were assessed during a 1-year follow-up period. 42% of the patients showed H. pylori infection. 82% resulted eradicated. Interestingly, 28% of the patietns reported a disappearance of migraine during the follow-up period. Moreover, a significant decrease of intensity, frequency and duration of the migraine attacks evaluated 2, 4, 6 and 12 months from H. pylori eradication was observed in the remaining patients. The beneficial effects of H. pylori eradication on migraine seem to be confirmed by this prolonged 1-year follow-up study. Received: 27 March 2000 / Accepted in revised form: 5 February 2001     

Nitric oxide: emerging implications for headache mechanics

The involvement of nitric oxide (NO) in the pathophysiology of primary headaches was suggested by several authors during the last decade. Migraine, cluster headache, tension headache, and cervicogenic headache have been extensively studied on the basis of NO donor headache pain. Different mechanisms seem to be involved in the generation of pain in these clearly different clinical head pain disorders. NO could control all the mechanisms leading to head pain. In migraine NO is correlated with endothelial activation, in cluster headache with a brainstem unravelling of the on/off regulatory clocks, in cervicogenic headache with a cytokine-dependent pain, and in tension-type headache with a sensitization of pain pathways at the spinal/trigeminal level. The next natural frontier in the study of pain in primary headaches seems to be the functional study of the relationship between NO and the immune regulatory system. Received: 30 Devember 2000 / Accepted in revised form: 9 April 2001     

Non Drug Treatment for Migraine Headache With Associated Raynaud''s Disease

SYNOPSIS
Patients presenting migraine headache associated with Raynaud's disease have been successfully treated in our clinic by using peripheral skin temperature biofeedback (BFB). The diagnosis of primary headache was established in all patients many years before Raynaud's disease appeared.
We selected 15 females for this study. Subjects were taken off all medication and patients' motivation for feedback therapy was ascertained. The time sequence of the peripheral skin temperature BFB sessions was the same as the one commonly followed at the Biofeedback Unit of the University of Rome Headache Service, i.e., two sessions per week in the first month of training, one session per week in the second, and subsequently one session every two weeks for four months, The use of a Headache Rating Scale for clinically evaluating BFB treatment for the relief of migraine attacks produced objective and comparable data suitable for statistical analyses, just as did the results of cold pressor tests studied before and after BFB training for evaluating the Raynaud's disease improvement.     

Computerized telethermographic assessment in migraine, with particular reference to the prodromal phase

We have studied the angular orbit and supraorbital arteries in 58 patients with classic migraine (36 females, 22 males; age (means), 43.5 years). A Dorex telethermograph apparatus, which utilizes the infrared radiations emitted by a patient, was used. The individual is placed at standard distance, and the temperature and humidity of the environment are kept constant. Three thermographic tests were performed in each patient: the first in basal condition, the other during the visual and/or sensory aura, and the last during the pain phase. The skin temperature levels decreased during the prodromal phase and increased during the migraine attack as compared with the levels obtained in basal conditions. There were significant asymmetries during the pain phase.     

Helicobacter pylori infection and vascular diseases

Helicobacter pylori infection has recently been associated to some organic functional vascular disorders and, both observational and interventional studies have been carried out. A correlation between Helicobacter pylori infection and ischaemic heart disease was first described in 1994. Recent data, moreover, indicate a role of the bacterium in some functional vascular disorders such as primary headache and primary Raynaud phenomenon; indeed, some patients following eradication of Helicobacter pylori showed a significant improvement in the manifestations of these diseases. The host immune response against the bacterium may play an important role in the pathogenesis of vascular disorders, probably through a chronic stimulation of the release of vasoactive substances, such as cytokines, prostaglandins and others. However, various confounding factors such as co-infections, genetic and immunological host-factors, different strains of Helicobacter pylori or other may influence the data. Well designed case/control and randomized interventional studies are still needed to assess the real role of Helicobacter pylori in vascular disorders.