natriuretic-peptide--brain and Migraine-Disorders

Purinergic P2X3 receptors (P2X3Rs) play an important role in pain pathologies, including migraine. In trigeminal neurons, P2X3Rs are constitutively downregulated by endogenous brain natriuretic peptide (BNP). In a mouse knock-in (KI) model of familial hemiplegic migraine type-1 with upregulated calcium CaV2.1 channel function, trigeminal neurons exhibit hyperexcitability with gain-of-function of P2X3Rs and their deficient BNP-mediated inhibition. We studied whether the absent BNP-induced control over P2X3Rs activity in KI cultures may be functionally expressed in altered firing activity of KI trigeminal neurons. Patch-clamp experiments investigated the excitability of wild-type and KI trigeminal neurons induced by either current or agonists for P2X3Rs or transient receptor potential vanilloid-1 (TRPV1) receptors. Consistent with the constitutive inhibition of P2X3Rs by BNP, sustained pharmacological block of BNP receptors selectively enhanced P2X3R-mediated excitability of wild-type neurons without affecting firing evoked by the other protocols. This effect included increased number of action potentials, lower spike threshold and shift of the firing pattern distribution toward higher spiking activity. Thus, inactivation of BNP signaling transformed the wild-type excitability phenotype into the one typical for KI. BNP receptor block did not influence excitability of KI neurons in accordance with the lack of BNP-induced P2X3R modulation. Our study suggests that, in wild-type trigeminal neurons, negative control over P2X3Rs by the BNP pathway is translated into tonic suppression of P2X3Rs-mediated excitability. Lack of this inhibition in KI cultures results in a hyperexcitability phenotype and might contribute to facilitated trigeminal pain transduction relevant for migraine.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Capsaicin; Cells, Cultured; Cerebellar Ataxia; Disease Models, Animal; Electric Stimulation; Mice, Transgenic; Migraine Disorders; Natriuretic Peptide, Brain; Neural Inhibition; Neurons; Neurotransmitter Agents; Patch-Clamp Techniques; Peptides, Cyclic; Receptors, Atrial Natriuretic Factor; Receptors, Purinergic P2X3; Trigeminal Ganglion; TRPV Cation Channels

Numerous studies suggest an increased vascular risk in patients with migraine, in particular in those with aura. A possible link between both conditions might be a dysfunction of the vascular endothelium. This observational study analyzed the endothelial markers angiopoietin-1, angiopoietin-2, Tie-2, sFlt-1 and NT-proBNP for the first time in migraineurs, patients with other primary headache disorders and healthy controls.. Patients with episodic migraine with and without aura, episodic cluster headache, tension-type headache and healthy controls were included. Blood samples were obtained during migraine attacks and headache-free periods in migraineurs, in and out of bout in cluster headache and during headache-free periods in tension-type headache and healthy individuals to analyze markers of endothelial function.. No significant difference in endothelial markers between migraine, other headache disorders and healthy controls was detected. There was no significant difference between migraine attacks and headache-free intervals. Additionally, no distinction could be found between migraine with and without aura.. The endothelial markers analyzed do not display a characteristic pattern in different headache disorders especially migraine compared to healthy controls. The novel findings of our study indicate that factors other than endothelial dysfunction seem to be responsible for the at least statistical association of migraine with vascular disease.

Topics: Adult; Angiopoietin-1; Angiopoietin-2; Biomarkers; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Migraine Disorders; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Receptor, TIE-2; Vascular Endothelial Growth Factor Receptor-1

Although migraine has been related with an increased risk for ischemic stroke and cardiovascular events, there is insufficient data for role of pro-brain natriuretic peptide (pro-BNP) in migraine. In present case-control study, serum levels of pro-inflammatory (TNF-alpha, IL-1beta and IL-6) and anti-inflammatory cytokines (IL-2, and IL-10) of migraine patients were investigated to determine the role of cytokines and pro-BNP in migraine.. Sixty-four consecutive newly diagnosed migraine patients and 34 healthy controls were enrolled. Serum TNF-alpha, IL-1beta, IL-2, IL-6, IL-10 and pro-BNP levels were measured by using a chemiluminescence assay.. Migraine patients had significantly higher concentrations of IL-1beta and IL-6 compared with the healthy controls (for IL-1beta; 5.73 +/- 1.44 vs. 4.90 +/- 1.40 pg/mL, respectively, p = 0.006; for IL-6; 3.1 +/- 1.44 vs. 2.40 +/- 0.22 pg/mL, respectively, p = 0.007). The mean IL-10 levels were found to be significantly lower in migraine patients (3.38 +/- 2.93 pg/mL) than controls (6.76 +/- 1.48 pg/mL) (p = 0.007). There were no differences in TNF-alpha (27.2 +/- 48.1 vs. 15.4 +/- 0.7) and IL-2 (1017 +/- 661 vs. 1153 +/- 228) levels between patients with migraine and healthy controls. Migraine patients had higher concentrations of pro-BNP compared with healthy controls (27.0 +/- 28.0 versus 13.2 +/- 8.6, p = 0.006).. Migraine patients have higher serum IL-1beta and IL-6 levels, and lower IL-10 levels than healthy subjects. These findings support that cytokines may be related to neurogenic inflammation in the pathogenesis of migraine. Also, increased pro-BNP may indicate to preclinical cardiac involvement in patients with migraine.

Topics: Adolescent; Adult; Biomarkers; Cytokines; Female; Humans; Male; Middle Aged; Migraine Disorders; Natriuretic Peptide, Brain; Peptide Fragments