Electrical stimulation of the superior sagittal sinus suppresses A-type K+ currents and increases P/Q- and T-type Ca2+ currents in rat trigeminal ganglion neurons.

BACKGROUND: Migraine is a debilitating neurological disorder involving abnormal trigeminovascular activation and sensitization. However, the underlying cellular and molecular mechanisms remain unclear. METHODS: A rat model of conscious migraine was established through the electrical stimulation (ES) of the dural mater surrounding the superior sagittal sinus. Using patch clamp recording, immunofluorescent labelling, enzyme-linked immunosorbent assays and western blot analysis, we studied the effects of ES on sensory neuronal excitability and elucidated the underlying mechanisms mediated by voltage-gated ion channels. RESULTS: The calcitonin gene-related peptide (CGRP) level in the jugular vein blood and the number of CGRP-positive neurons in the trigeminal ganglia (TGs) were significantly increased in rats with ES-induced migraine. The application of ES increased actional potential firing in both small-sized IB4-negative (IB4-) and IB4+ TG neurons. No significant changes in voltage-gated Na+ currents were observed in the ES-treated groups. ES robustly suppressed the transient outward K+ current (IA) in both types of TG neurons, while the delayed rectifier K+ current remained unchanged. Immunoblot analysis revealed that the protein expression of Kv4.3 was significantly decreased in the ES-treated groups, while Kv1.4 remained unaffected. Interestingly, ES increased the P/Q-type and T-type Ca2+ currents in small-sized IB4- TG neurons, while there were no significant changes in the IB4+ subpopulation of neurons. CONCLUSION: These results suggest that ES decreases the IA in small-sized TG neurons and increases P/Q- and T-type Ca2+ currents in the IB4- subpopulation of TG neurons, which might contribute to neuronal hyperexcitability in a rat model of ES-induced migraine.

First study on the peptidergic innervation of the brain superior sagittal sinus in humans.

The superior sagittal sinus (SSS) of the mammalian brain is a pain-sensitive intracranial vessel thought to play a role in the pathogenesis of migraine headaches. Here, we aimed to investigate the presence and the potential co-localization of some neurotransmitters in the human SSS. Immunohistochemical and double-labeling immunofluorescence analyses were applied to paraformaldehyde-fixed, paraffin-embedded, coronal sections of the SSS. Protein extraction and Western blotting technique were performed on the same material to confirm the morphological data. Our results showed nerve fibers clustered mainly in large bundles tracking parallel to the longitudinal axis of the sinus, close in proximity to the vascular endothelium. Smaller fascicles of fibers encircled the vascular lumen in a spiral fashion, extending through the subendothelial connective tissue. Isolated nerve fibers were observed around the openings of bridging veins in the sinus or around small vessels extending into the perisinusal dura. The neurotransmitters calcitonin gene related peptide (CGRP), substance P (SP), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), and neuropeptide Y (NPY) were found in parietal nerve structures, distributed all along the length of the SSS. Overall, CGRP- and TH-containing nerve fibers were the most abundant. Neurotransmitters co-localized in the same fibers in the following pairs: CGRP/SP, CGRP/NOS, CGRP/VIP, and TH/NPY. Western blotting analysis confirmed the presence of such neurosubstances in the SSS wall. Overall our data provide the first evidence of the presence and co-localization of critical neurotransmitters in the SSS of the human brain, thus contributing to a better understanding of the sinus functional role.

Structural and mechanical characterisation of bridging veins: A review.

Bridging veins drain the venous blood from the cerebral cortex into the superior sagittal sinus (SSS) and doing so they bridge the subdural space. Despite their importance in head impact biomechanics, little is known about their properties with respect to histology, morphology and mechanical behaviour. Knowledge of these characteristics is essential for creating a biofidelic finite element model to study the biomechanics of head impact, ultimately leading to the improved design of protective devices by setting up tolerance criteria. This paper presents a comprehensive review of the state-of-the-art knowledge on bridging veins. Tolerance criteria to prevent head injury through impact have been set by a number of research groups, either directly through impact experiments or by means of finite element (FE) simulations. Current state-of-the-art FE head models still lack a biofidelic representation of the bridging veins. To achieve this, a thorough insight into their nature and behaviour is required. Therefore, an overview of the general morphology and histology is provided here, showing the clearly heterogeneous nature of the bridging vein complex, with its three different layers and distinct morphological and histological changes at the region of outflow into the superior sagittal sinus. Apart from a complex morphology, bridging veins also exhibit complex mechanical behaviour, being nonlinear, viscoelastic and prone to damage. Existing material models capable of capturing these properties, as well as methods for experimental characterisation, are discussed. Future work required in bridging vein research is firstly to achieve consensus on aspects regarding morphology and histology, especially in the outflow cuff segment. Secondly, the advised material models need to be populated with realistic parameters through biaxial mechanical experiments adapted to the dimensions of the bridging vein samples. Finally, updating the existing finite element head models with these parameters will render them truly biofidelic, allowing the establishment of accurate tolerance criteria and, ultimately, better head protection devices.