Person:

Curto, Martina

Background: Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls. Methods: We assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). Results: LC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (−32 %), KYNA (−25 %), 3-HK (−49 %), 3-HANA (−63 %), 5-HIAA (−36 %) and QUINA (−80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively). Conclusions: These findings suggest that in migraine KYN is unidirectionally metabolized into ANA at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.

Background: The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls. Method We assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Results: LC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH. Conclusion: The reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

The efficacy and safety of OnabotulinumtoxinA 155-195 U (BOTOX®) in adults with chronic migraine (CM) were demonstrated in both the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies. However, data about its long-term efficacy and safety in clinical settings are scanty. Therefore, the objective of this study is to evaluate OnabotulinumtoxinA 155 U treatment in patients affected with CM and co-morbid medication overuse headache (MOH) over 2-year analysis. We prospectively evaluated 155 CM and MOH affected patients started on OnabotulinumtoxinA 155U (PREEMPT injection paradigm) between October 2010 and November 2011 and followed-up for 2 years. All patients failed to positively respond to previous multiple preventive therapies that were withdrawn before starting OnabotulinumtoxinA. Headache days, migraine days, acute pain medication intake days and Headache Impact Test (HIT)-6 score were used as efficacy measures, whereas safety was evaluated with side effects occurrence during the treatment phase. Baseline data were collected from patients headache diary referred to the previous month, and patients were evaluated every 3 months at the time of each injection. OnabotulinumtoxinA 155U significantly reduced the number of headache and migraine days (p < 0.001), acute pain medication intake days (p < 0.001) and HIT-6 score (p < 0.001) when compared with the baseline data. The reduction was significant after the first injection (p < 0.001), and gradually increased during the 2 years of treatment. Treatment related adverse events were transient and mild-moderate (e.g. headache, injection-site pain, eyelid ptosis, musculoskeletal weakness). This prospective 2-years analysis of efficacy and safety of long-term treatment with OnabotulinumtoxinA 155 U in patients affected with CM and MOH confirms the efficacy data from previous Randomized Clinical Trials for CM prophylaxis. Moreover, here we demonstrate that OnabotulinumtoxinA can be safely used for the long-term treatment of MOH comorbidity in CM. Electronic supplementary material The online version of this article (doi:10.1186/s40064-015-1636-9) contains supplementary material, which is available to authorized users.