Serum L-arginine and dimethylarginine levels in migraine patients with brain white matter lesions

Background/Aim: Migraine is a risk factor for the formation of silent brain white matter lesions (WMLs) that are possibly ischemic in nature. Although dysfunction of the L-arginine/nitric oxide (NO) pathway has been associated with oxidative stress and endothelial dysfunction in migraine, its role in WML development has not been specifically investigated. Thus, this prospective study aimed to measure the serum concentrations of the NO substrate L-arginine, the NO synthase inhibitor asymmetric dimethylarginine (ADMA), and the L-arginine transport regulator symmetric dimethylarginine (SDMA) in migraine patients in a headache-free period. Methods: All participants underwent MR imaging to assess for the presence of WMLs on fluid-attenuated inversion recovery imaging. Altogether 109 migraine patients (43 with lesions, 66 without lesions) and 46 control individuals were studied. High-performance liquid chromatography was used to quantify L-arginine, ADMA and SDMA serum concentrations. Migraine characteristics were investigated, and participants were screened for risk factors that can lead to elevated serum ADMA levels independent of migraine. Results: Migraine patients and controls did not differ in regard to vascular risk factors. Migraineurs with WMLs had a longer disease duration (p<0.001) and a higher number of lifetime headache attacks (p=0.005) than lesion-free patients. Higher L-arginine serum levels were found in both migraine subgroups compared to controls (p<0.001). Migraine patients with WMLs showed higher ADMA concentrations than lesion-free patients and controls (p<0.001, for both). In migraineurs, the presence of WMLs, aura and increasing age proved to be significant predictors of increased ADMA levels (p=0.008, 0.047 and 0.012, respectively). SDMA serum levels of lesional migraineurs were higher than in nonlesional patients (p<0.001). The presence of lesions and increasing age indicated an increased SDMA level (p=0.017 and 0.001, respectively). Binary logistic regression analysis showed that ADMA level (p=0.006), increasing age (p=0.017) and the total number of lifetime migraine attacks (p=0.026) were associated with an increased likelihood of exhibiting WMLs. There was no significant effect of age on ADMA and SDMA concentrations in controls. Conclusions: Elevated ADMA levels may impact the pathogenesis of migraine-related WMLs by influencing cerebrovascular autoregulation and vasomotor reactivity. Higher SDMA concentrations may indirectly influence NO synthesis by reducing substrate availability. Elevated L-arginine serum levels might reflect an increased demand for NO synthesis.