Induction of migraine-like headache, but not aura, by cilostazol in patients with migraine with aura.

Whether migraine headache and migraine aura share common pathophysiological mechanisms remains to be understood. Cilostazol causes cAMP accumulation and provokes migraine-like headache in migraine patients without aura. We investigated if cilostazol induces aura and migraine-like headache in patients with migraine with aura and alters peripheral endothelial function and levels of endothelial markers. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 12 patients exclusively had attacks of migraine with aura) received 200 mg cilostazol (Pletal®) or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. Peripheral endothelial function was assessed by digital pulse amplitude tonometry using EndoPAT2000, and endothelial markers (VCAM1, E-selectin, and VEGFA) were measured. After administration of cilostazol, 14 patients (88%) experienced headache compared with six patients (38%) after placebo (P = 0.009). The headache in 12 patients (75%) after cilostazol and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (P = 0.0002). Patients reported that the attack mimicked the headache phase during their usual migraine attacks. However, aura symptoms were elicited in one patient after cilostazol and one patient after placebo. Further, endothelial function, as assessed by peripheral arterial tonometry, and endothelial markers were not significantly altered by cilostazol. Accumulation of cAMP by cilostazol induces migraine-like headache, but not aura, in patients with migraine with aura, even in those who exclusively reported attacks of migraine with aura in their spontaneous attacks. These findings further support dissociation between the aura and the headache phase with a yet unknown trigger for the aura and link between aura and headache. In addition, cilostazol administration did not significantly alter endothelial function, as assessed by peripheral arterial tonometry, or the endothelial markers, VCAM1, E-selectin, and VEGFA. However, post hoc analyses showed that our study was statistically underpowered for these outcomes.

Validation of Repeated Endothelial Function Measurements Using EndoPAT in Stroke.

BACKGROUND: Decreased endothelial function (EF) may be a prognostic marker for stroke. Measuring pharmacological effects on EF may be of interest in the development of personalized medicine for stroke prevention. In this study, we assessed the reliability of repeated EF measurements using a pulse amplitude tonometry technology in acute stroke patients. Similarly, reliability was tested in healthy subjects devoid of vascular disease to estimate reactivity and reliability in a younger non-stroke population. MATERIALS AND METHODS: EF was assessed using the EndoPAT2000 in 20 healthy volunteers (men 50%, mean age 35.85 ± 3.47 years) and 21 stroke patients (men 52%, mean age 66.38 ± 2.85 years, and mean NIHSS 4.09 ± 0.53) under standardized conditions. EF was measured as the reactive hyperemia index (RHI), logarithm of RHI (lnRHI), and Framingham RHI (fRHI). Measurements were separated by 1.5 and 24 h to assess same-day and day-to-day reliability, respectively. RESULTS: Fair to moderate correlations of measurements [intraclass correlation coefficient (ICC)same-day 0.29 and ICCday-to-day 0.52] were detected in healthy subjects. In stroke patients, we found moderate to substantial correlation of both same-day and day-to-day repeated measurements (ICCsame-day 0.40 and ICCday-to-day 0.62). fRHI compared with RHI and lnRHI showed best reliability. CONCLUSION: Repeated measurements of fRHI in stroke patients show moderate reliability on same-day and substantial on day-to-day measurements. Likewise, in healthy subjects there was substantial reliability on day-to-day measurement, but only moderate on same-day measurements. In general, day-to-day correlation of repeated EF measurements was far better than that of same-day measurements, which ranged from poor to moderate depending on the specific outcome measure of EF. A possible carryover effect should be considered if same-day repeated testing of drug effects is applied in future studies.

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes.

BACKGROUND: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes. RESULTS: The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARδ agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARγ coactivator-1α. CONCLUSIONS: UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA.