Genetics of migraine and pharmacogenomics: some considerations

Migraine is a complex disorder caused by a combination of genetic and environmental factors

Differential effects of unilateral magnetic cortical stimulation on reaction time

Data from patients with brain lesions suggested that the right hemisphere is involved in the intention of simple movements, while the left is involved in more complex tasks. The contributions of each hemisphere to a reaction time (RT) task were assessed with cortical magnetic stimulation in five healthy right-handed subjects. Subjects were asked to push buttons with both hands as fast as possible after a visual start stimulus. At three different delays (25, 50 and 75 ms) after the start signal, a magnetic stimulus of 20, 40 or 60% of maximum intensity was given to either the right or the left hemisphere. Delay, intensity and side of stimulation varied in random order. Repeated measures analysis of variance showed two main effects: firstly, RT was longer on the body side innervated by the stimulated than by the non-stimulated hemisphere. Thus, cortical stimulation delayed the execution of a motor task, as shown previously. Secondly, there was an interaction between side of stimulation and delay of the cortical stimulus. At a delay of 25 ms, right-sided stimulation resulted in longer RTs than left-sided stimulation. At delays of 50 and 75 ms, the reverse proved true. In both cases the effect held for both hands. According to these results, the right hemisphere is predominantly involved in the early phases of an RT task, while the left hemisphere is more involved in later phases of processing. The results show that cortical magnetic stimulation can be used to investigate differential contributions of the hemispheres to motor tasks in viv

Association study between clinical response to rizatriptan and some candidate genes

The aim of this study was to test genetic differences in the clinical response to rizatriptan in patients affected by migraine without aura. These genetic differences could be explained by various genes, the HTR1B, encoding the 5-HT(1) receptor subtype, MAOA gene that encodes the monoamino-oxidase, the main metabolic enzyme of this triptan, SLC6A4 (gene encoding the serotonin transporter) and DRD(2) (gene encoding the D(2) receptor), both involved in the pathogenesis of migraine. Fifty unrelated patients affected by migraine without aura (IHS) were included. Patients were divided into two groups (responders and non-responders) according to clinical response. Thirty-one out of fifty patients responded to rizatriptan. A significant difference among the two groups was observed in both allele (p=0.02) and genotype distribution (p=0.03) of DRD2/NcoI. The significant association with the DRD2/NcoI polymorphism in responders suggested that the DRD2/NcoI C allele may be considered a susceptibility factor heralding a good response to rizatriptan

Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane.

1. The antimigraine drug, sumatriptan, contracts the human coronary artery and, in some patients, elicits chest symptoms (e.g. pressure and pain), particularly after subcutaneous administration. We studied the effects of the thromboxane A2 (TxA2) analogue, U46619 and endothelin-1 on contractile responses to sumatriptan in the human isolated coronary artery as well as the role of endogenously produced TxA2 and endothelin-1 in contractions evoked by sumatriptan. 2. In the presence of U46619 (1 and 3 nM), mean concentration-response curves to sumatriptan in the human coronary artery were shifted vertically due to the initial contraction by U46619, but when this initial contraction was subtracted from the response to sumatriptan, no significant augmentation was observed. However, analysis of the degree of augmentation in individual arterial segments revealed that the augmentation was variable and related inversely to the Emax of sumatriptan in the absence of U46619 (r = 0.78 and 0.81 for 1 and 3 nM, respectively; P < 0.05). 3. Treatment with the TxA2 receptor antagonist, SQ30741 (100 nM), or incubation of vessel segments with aspirin (10 microM), significantly reduced responses to sumatriptan; in aspirin-treated vessel segments, SQ30741 failed to decrease further the contractions to sumatriptan. The decrease in Emax of sumatriptan by both SQ30741 and aspirin correlated significantly with the Emax of sumatriptan without SQ30741 (r = 0.74; P < 0.01) or aspirin (r = 0.94; P < 0.01). In aspirin-treated vessel segments, responses to sumatriptan were significantly augmented in the presence of U46619 (3 nM; P < 0.05). 4. The specificity of SQ30741 was demonstrated by its ability to antagonize coronary artery contractions to U46619 (pA2: 7.54 +/- 0.30), but not endothelin-1. Similarly, incubation with aspirin (10 microM) did not affect contractile responses to endothelin-1, but significantly reduced TxA2 production in coronary artery segments as judged by a decrease in thromboxane B2 (TxB2) from 4.77 +/- 0.98 to 1.38 +/- 0.36 ng g-1 2 h-1. 5. Endothelin-1 (1 nM) did not significantly augment contractions to sumatriptan; there was also no relationship between the degree of augmentation and the control Emax of sumatriptan in the absence of endothelin-1. Furthermore, unlike SQ30741 or aspirin, a high concentration (100 nM) of the non-selective ETA/ETB receptor antagonist, SB 209670, failed to affect contractile responses to sumatriptan. However, SB 209670 potently antagonized coronary artery contractions induced by endothelin-1 with a pA2 of 8.84 +/- 0.32. 6. Compared to control vascular segments, endothelial denudation did not reduce TxA2 production (with endothelium = 2.56 +/- 1.38 vs. without endothelium = 12.32 +/- 4.94 ng TxB2 g-1 2 h-1), suggesting that the production of TxA2 is not confined to the endothelium. The sumatriptan-induced contractions were also unaffected by endothelial denudation. 7. The results of the present study suggest that endogenously produced TxA2 enhances contractions to sumatriptan in the human isolated coronary artery. Such a mechanism may play a role in causing chest symptoms after sumatriptan by potentiating coronary vascular contraction by sumatriptan in vivo

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 mu g . kg(-1)], i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean +/- S.E.M. dose of GMC2021 eliciting a 50% decrease (ED(50)) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 +/- 0.3 mu mol . kg(-1) and the highest dose (1000 mu g . kg(-1)) produced a 67 +/- 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED(50): 0.16 mu mol . kg(-1) i.v.). Compared to sumatriptan (pD(2): 6.12 +/- 0.15; E(max): 31.3 +/- 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD(2): 5.45 +/- 0.2; E(max): 21.0 +/- 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects