Functional characterization of the dural sinuses as a neuroimmune interface.

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells. This surveillance is enabled by endothelial and mural cells forming the sinus stromal niche. T cell recognition of CSF-derived antigens at this site promoted tissue resident phenotypes and effector functions within the dural meninges. These findings highlight the critical role of dural sinuses as a neuroimmune interface, where brain antigens are surveyed under steady-state conditions, and shed light on age-related dysfunction and neuroinflammatory attack in animal models of multiple sclerosis.

Does the prone sleeping position affect the intracranial dural venous flow?

PURPOSE: There are few studies documenting the effect of posture on intracranial dural venous flow. The aim of the present study was to explore alterations caused by the prone position using magnetic resonance (MR) venography. METHODS: A total of eight patients (five men and three women) underwent non-contrast MR venography in both supine and prone positions. RESULTS: In the prone position, an increase in intracranial dural venous flow was found in all patients in the non-dominant transverse and sigmoid sinuses. An increase in venous flow to the straight sinus was observed in 75% of the patients. Flow to the superior ophthalmic vein decreased in three patients. No postural flow alterations were observed in any of the patients in the superior sagittal, dominant transverse, and sigmoid sinuses. CONCLUSION: Based on results of the study, in the prone sleeping position, part of the intracranial venous flow may be preferentially drained through the straight and non-dominant transverse sinuses.

Cranial biomechanics, bite force and function of the endocranial sinuses in Diprotodon optatum, the largest known marsupial.

The giant extinct marsupial Diprotodon optatum has unusual skull morphology for an animal of its size, consisting of very thin bone and large cranial sinuses that occupy most of the internal cranial space. The function of these sinuses is unknown as there are no living marsupial analogues. The finite element method was applied to identify areas of high and low stress, and estimate the bite force of Diprotodon to test hypotheses on the function of the extensive cranial sinuses. Detailed three-dimensional models of the cranium, mandible and jaw adductor muscles were produced. In addition, manipulations to the Diprotodon cranial model were performed to investigate changes in skull and sinus structure, including a model with no sinuses (sinuses 'filled' with bone) and a model with a midsagittal crest. Results indicate that the cranial sinuses in Diprotodon significantly lighten the skull while still providing structural support, a high bite force and low stress, indicating the cranium may have been able to withstand higher loads than those generated during feeding. Data from this study support the hypothesis that pneumatisation is driven by biomechanical loads and occurs in areas of low stress. The presence of sinuses is likely to be a byproduct of the separation of the outer surface of the skull from the braincase due to the demands of soft tissue including the brain and the large jaw adductor musculature, especially the temporalis. In very large species, such as Diprotodon, this separation is more pronounced, resulting in extensive cranial sinuses due to a relatively small brain compared with the size of the skull.

In vivo analysis of physiological 3D blood flow of cerebral veins.

OBJECTIVES: To visualize and quantify physiological blood flow of intracranial veins in vivo using time-resolved, 3D phase-contrast MRI (4D flow MRI), and to test measurement accuracy. METHODS: Fifteen healthy volunteers underwent repeated ECG-triggered 4D flow MRI (3 Tesla, 32-channel head coil). Intracranial venous blood flow was analysed using dedicated software allowing for blood flow visualization and quantification in analysis planes at the superior sagittal, straight, and transverse sinuses. MRI was evaluated for intra- and inter-observer agreement and scan-rescan reproducibility. Measurements of the transverse sinuses were compared with transcranial two-dimensional duplex ultrasound. RESULTS: Visualization of 3D blood flow within cerebral sinuses was feasible in 100 % and within at least one deep cerebral vein in 87 % of the volunteers. Blood flow velocity/volume increased along the superior sagittal sinus and was lower in the left compared to the right transverse sinus. Intra- and inter-observer reliability and reproducibility of blood flow velocity (mean difference 0.01/0.02/0.02 m/s) and volume (mean difference 0.0002/-0.0003/0.00003 l/s) were good to excellent. High/low velocities were more pronounced (8 % overestimation/9 % underestimation) in MRI compared to ultrasound. CONCLUSIONS: Four-dimensional flow MRI reliably visualizes and quantifies three-dimensional cerebral venous blood flow in vivo and is promising for studies in patients with sinus thrombosis and related diseases. KEY POINTS: • 4D flow MRI can be used to visualize and quantify physiological cerebral venous haemodynamics • Flow quantification within cerebral sinuses reveals high reliability and accuracy of 4D flow MRI • Blood flow volume and velocity increase along the superior sagittal sinus • Limited spatial resolution currently precludes flow quantification in small cerebral veins.

The inferior petrosal sinus: a comprehensive review with emphasis on clinical implications.

INTRODUCTION: The inferior petrosal sinus is an important component of the cerebral venous system with implications in diagnosis and treatment of a variety of diseases such as Cushing's disease, carotid cavernous, and dural arteriovenous fistulas. METHODS: This manuscript will review the anatomy, embryology, and clinical implications of the inferior petrosal sinus. CONCLUSIONS: Knowledge of the inferior petrosal sinus is of great importance for open surgical approaches to the skull base and endovascular access to the cavernous sinus and sellar region.

The Neanderthal face is not cold adapted.

Many morphological features of the Pleistocene fossil hominin Homo neanderthalensis, including the reputed large size of its paranasal sinuses, have been interpreted as adaptations to extreme cold, as some Neanderthals lived in Europe during glacial periods. This interpretation of sinus evolution rests on two assumptions: that increased craniofacial pneumatization is an adaptation to lower ambient temperatures, and that Neanderthals have relatively large sinuses. Analysis of humans, other primates, and rodents, however, suggests that the first assumption is suspect; at least the maxillary sinus undergoes a significant reduction in volume in extreme cold, in both wild and laboratory conditions. The second assumption, that Neanderthal sinuses are large, extensive, or even 'hyperpneumatized,' has held sway since the first specimen was described and has been interpreted as the causal explanation for some of the distinctive aspects of Neanderthal facial form, but has never been evaluated with respect to scaling. To test the latter assumption, previously published measurements from two-dimensional (2D) X-rays and new three-dimensional (3D) data from computed tomography (CT) of Neanderthals and temperate-climate European Homo sapiens are regressed against cranial size to determine the relative size of their sinuses. The 2D data reveal a degree of craniofacial pneumatization in Neanderthals that is both commensurate with the size of the cranium and comparable in scale with that seen in temperate climate H. sapiens. The 3D analysis of CT data from a smaller sample supports this conclusion. These results suggest that the distinctive Neanderthal face cannot be interpreted as a direct result of increased pneumatization, nor is it likely to be an adaptation to resist cold stress; an alternative explanation is thus required.

The relationship between parasagittal and falcine meningiomas and the superficial cortical veins: a virtual reality study.

OBJECTIVES: Surgery for parasagittal and falcine meningiomas requires meticulous preservation of the cortical veins that surround the tumour; thus, knowledge of the relevant venous anatomy would be extremely helpful during surgery. METHODS: This study utilises virtual reality technology to determine the number, size and disposition of the veins in relation to the tumour in 8 patients with parasagittal and falcine meningiomas. The same data were also collected from the scans of 8 normal subjects and compared with the data from the meningioma patients. RESULTS: Our results show that the average number of veins is comparable in the tumour and control groups, and that the number of veins on either side does not differ significantly for both groups. On measurement, the size of the veins is approximately the same on either side of the superior sagittal sinus for both the control and the tumour groups. It was also observed that regardless of size, most of the parasagittal and falcine meningiomas demonstrated no significant anatomical distortion effects on the adjacent venous structures, with the exception of one parasagittal meningioma with invasion of the superior sagittal sinus and concomitant engulfment of the draining veins. CONCLUSION: Data from a larger population would have to be collected in order to determine the effect of the growth of these tumours on the surrounding venous anatomy. With virtual reality technology, the parasagittal veins are clearly discerned, and knowing their location and relationship to the tumour would contribute towards safe and effective surgery.

Endoscopic and microscopic anatomy of the superior sagittal sinus and torcular herophili.

Surgery of the superior sagittal sinus (SSS) is a challenging areas for neurosurgeons. To better understand the anatomy of the SSS, we examined the chordae and arachnoid granulations in the lumen of the SSS and torcular herophili with the aid of an endoscope and a microscope, and re-evaluated the role of the chordae Willisii in preventing blood backflow. We prepared 10 SSS from fresh human cadavers during autopsies. After the cranial vaults were removed, an endoscope was inserted into the lumen of the sinus to examine the structures and morphological features of the chordae Willisii, and the topographic distribution of the arachnoid granulations. The sinuses were subsequently opened using standard anatomical methods and the intraluminal structures of the dural sinus were subjected to microanatomic analysis. In another five formalin-embalmed cadaver heads, blue latex was injected from the posterior end of the SSSs to observe filling of the SSS tributaries. We identified three types of chordae in the lumen of the SSS: valve-like chordae (48.3% of all chordae), followed by trabecular (31.5%) and laminar (20.2%) chordae. The laminar chordae at the posterior end of the SSS divide the sinus into two separate channels of different sizes. Similar structures were also seen in the lumen of the torcular herophili. The majority of arachnoid granulations were found as digitations in the lumen at the lateral wall or lateral recess of the middle segment of the SSS. Microscopic examination of the intraluminal structures of the SSS confirmed endoscopic findings. In the injection test we found that the SSS tributaries could be filled retrogradely with artificial dye, suggesting that the function of valve-like chordae in preventing the backflow of blood is restricted only to physiological conditions. Thus, we could visualize and examine endoscopically the intact intraluminal structures of the SSS, which may have therapeutic or diagnostic significance.

A Preliminary Study of Neonatal Cranial Venous System by Color Doppler.

AIM: To present anatomic data in the ultrasound planes for the identification of the major veins and the venous sinuses in cerebrum and to establish the sonographic normal reference values for the visualization of vein vessels and vein sinuses and blood flow velocities. METHODS: This study involved 55 healthy full-term neonates for transfontanellar color Doppler sonography. The imaging included both sagittal and coronal planes with LA332E probe, supplemented with PA240 probe as necessary. As low as reasonably achievable (ALARA) principle was obeyed, limiting Doppler exposure time and maximizing signal intensity by increasing gain rather than outputting transducer power settings. The output power was kept at a minimum level consistent with recording an adequate signal. Keeping the newborns in calm state, the total examination time which every neonate required was less than 5 min. All images were stored also in a workstation for further analysis. The description statistics and t-test for statistical analysis were used. RESULT: In all studied cases (100% cases), subependymal veins (SV), internal cerebral veins (ICV), Galen vein (GV), straight sinus (SS), superior sagittal sinus (SSS), and transverse sinuses (TS) were visualized. The visualization percentages of inferior sagittal sinus (ISS) or basal veins/Rosenthal veins (BV/RV) were lower than 100%. Based on vessel visualization percentage from high to low, the vessels were ordered as follows: SV, ICV, BV, SS, TS, ISS, and SSS. In SSS and TS, the pulsation percentage was 100%. The descending percentages of vessel pulsation were noted in SS, BV, ICV, and SV. On the basis of the mean of maximum velocities of the vessels from low to high, the vessels were ordered as follows: ISS, BV-L, BV-R, ICV-R, ICV-L, SV-L, SV-R, SSS, TS-L, TS-R, and SS. CONCLUSION: The measurements percent of visualization of cerebral deep veins was higher than the percent of cerebral venous sinuses. The pulsation percent of measurement and the velocities of cerebral venous sinuses were absolutely higher than the cerebral deep venous system. The pairs of vascular blood flow velocities were nonsignificantly different from one another.

Morphological study of sinus flow in the confluence of sinuses.

The confluence of sinuses (CS; torcular herophili) is represented by the junction of the superior sagittal (SSS), straight (SS), occipital (OS), and two transverse sinuses (TS). The objective of this study was to interpret sinus flow around the CS by morphological investigation of the sinuses. This study is based on visual examination of dural venous sinuses in the region of the CS in 31 adult cadavers. In the inflow zone, we examined the direction of SSS and SS flow. In the communication zone, we examined the extent to which outflow sinuses communicate with other sinuses. In the outflow zone, we used the diameters of outflow sinuses to determine anatomical dominance. The SSS entered the CS via the right TS in 16 cases (51.6%) and via the center of the CS in 14 cases (45.2%). The SS entered via the center of the CS in 18 cases (58.1%) and via the left TS in 11 cases (35.5%). Outflow sinuses communicated freely in 26 cases (83.8%) and communicated partially in five cases (16.2%). Partial communication was the result of a septate CS. In terms of outflow, the right TS was dominant in 11 cases (35.5%), and in 18 cases (58.1%), outflow was symmetrical. The direction of SSS inflow was different from that of SS inflow, and partial communication was observed in five cases (16.1%). Therefore, the presence of a septum may be considered an anatomical factor, with implications in diagnosis or in the sacrifice of the outflow sinus of the CS.

Prediction of the jugular venous waveform using a model of CSF dynamics.

BACKGROUND AND PURPOSE: We have previously reported a model of cerebral hydrodynamics in the form of an equivalent electrical circuit. The aim of this work was to demonstrate that the model could predict venous flow patterns seen in the superior sagittal sinus (SSS), straight sinus (STS), and jugular vein (JV) in normal volunteers. MATERIALS AND METHODS: An electrical equivalence model of CSF and cerebral blood flow was fitted to measured arterial and CSF data from 16 healthy volunteers. Predictions of the venous outflow waveform derived from the model were compared with measured venous flows in the SSS, STS, and JV. RESULTS: The model accurately predicted the measured jugular waveform. The measured waveforms from SSS and STS showed a less pronounced and delayed systolic peak compared with the predicted outflow. The fitted bulk model parameters provided relative values that correspond approximately to the impedance of arterial capillaries (1.0), cerebral aqueduct ( approximately 0), venous capillaries ( approximately 0), and arteries (0.01) and for the elastic capacitance of the ventricles (4.11), capillaries ( approximately 0), and veins (271). The elastic capacitance of the major cerebral arteries was large and could not be accurately determined. CONCLUSIONS: We have confirmed the ability of the model to predict the venous waveforms in healthy persons. The absence of any statistically significant component of the venous waveform not described by the model implies that measurements of venous flow could be used to constrain further the model-fitting process.

Morphology, constraints, and scaling of frontal sinuses in the hartebeest, Alcelaphus buselaphus (Mammalia: Artiodactyla, Bovidae).

The frontal sinuses of bovid mammals display a great deal of diversity, which has been attributed to both phylogenetic and functional influences. In-depth study of the hartebeest (Alcelaphus buselaphus), a large African antelope, reveals a number of previously undescribed details of frontal sinus morphology. In A. buselaphus, the frontal sinuses conform closely to the shape of the frontal bone, filling nearly the entire element. However, the horncores are never extensively pneumatized, contrasting with the condition seen in many other bovids. This evidence is inconsistent with the hypothesis that sinuses are opportunistic pneumatizing agents, suggesting that phylogenetic factors also play a role in determining sinus size. Both cranial sutures and neurovasculature appear to constrain the growth of sinuses in part. In turn, the sinus also affects the growth of the parietal; apparently this element is not truly pneumatized by the sinus in most cases, but the bone's shape changes under the influence of the sinus. Furthermore, the sinuses present relatively few struts when compared with the sinuses of some other bovids, such as Ovis. By adapting methods previously developed for measuring structural parameters of trabecular bone, it is possible to quantify certain aspects of sinus morphology. These include the number of bony struts within the sinus, the spacing of these struts, and the size of individual cavities within the sinus. Some differences in the number of struts are evident between subspecies. Similarly, significant differences occur in the relative number of struts between male and female A. buselaphus, which may be related to behavior. The volume of the sinus is strongly correlated with the size of the frontal, but less so with overall cranial size. This finding illustrates the importance of choosing variables carefully when comparing sinus sizes and growth between species.

Intracranial physiological calcifications in adults on computed tomography in Tabriz, Iran.

Intracranial physiological calcifications are unaccompanied by any evidence of disease and have no demonstrable pathological cause. They are often due to calcium and sometimes iron deposition in the blood vessels of different structures of the brain. Computed tomography (CT) is the most sensitive means of detection of these calcifications. The aim of this study was the assessment of intracranial physiological calcifications in adults. We studied 1569 cases ranging in age from 15 to 85 in Tabriz Imam Khomeini Hospital, Iran. These patients had a history of head trauma and their CT scan did not show any evidence of pathological findings. The structures evaluated consisted of (A) the pineal gland, (B) the choroid plexus, (C) the habenula, (D) the basal ganglia, (E) the tentorium cerebelli, sagittal sinus and falx cerebri, (F) vessels and (G) lens and other structures which could be calcified. Of the 1569 subjects, 71.0% had pineal calcification, 66.2% had choroid plexus calcification, 20.1% had habenular calcification, 7.3% had tentorium cerebelli, sagittal sinus or falx cerebri calcifications, 6.6% had vascular calcification, 0.8% had basal ganglia calcification and 0.9% had lens and other non-defined calcifications. In general, the frequency of intracranial physiological calcifications was greater in men than in women. All types of calcification increased at older ages except for lens and other non-defined calcifications. We evaluated all the cranial structures and determined percentages for all types of intracranial physiological calcification. These statistics can be used for comparing physiological and pathological intracranial calcifications. Moreover, these statistics may be of interest from the clinical perspective and are potentially of clinical use.

Use of Phase-Contrast MRA to Assess Intracranial Venous Sinus Resistance to Drainage in Healthy Individuals.

BACKGROUND AND PURPOSE: Resistance to blood flow in the cerebral drainage system may affect cerebral hemodynamics. The objective of the present study was to use phase-contrast MRA to quantify resistance to drainage of blood across branches of the venous sinus tree and to determine whether the resistance to drainage values correlated with internal jugular vein outflows. MATERIALS AND METHODS: We performed whole-head phase-contrast MRA and 2D phase-contrast MR imaging in 31 healthy volunteers. Vascular segmentation was applied to the angiograms, and the internal jugular vein velocities were quantified from the flow images. Resistance to drainage across branches of the venous sinus tree was calculated from the segmented angiograms, by using the Poiseuille equation for laminar flow. Correlations between the values of resistance to drainage and internal jugular vein outflow measurements were assessed by using the Spearman ρ. RESULTS: The overall mean resistance to drainage of the venous sinus tree was 24 ± 7 Pa s/cm3. The mean resistance to drainage of the right side of the venous sinus tree was 42% lower than that of the left side (P < .001). There were negative correlations between the values of resistance to drainage and internal jugular vein outflows on both the left side of the venous sinus tree (R = -0.551, P = .002) and the right side (R = -0.662, P < .001). CONCLUSIONS: Phase-contrast MRA is a noninvasive means of calculating the resistance to drainage of blood across the venous sinus tree. Our approach for resistance to drainage quantification may be of value in understanding alterations in the cerebral venous sinus drainage system.

Intracranial venous pressures under conscious sedation and general anesthesia.

INTRODUCTION: Venous outflow obstruction has been implicated in the pathophysiology of a subset of patients with idiopathic intracranial hypertension (IIH), and venous sinus stenting (VSS) has emerged as an effective treatment. However, the effect of anesthesia on venous sinus pressure measurements is unpredictable. A more thorough understanding of the effect of the level of anesthesia on intracranial venous pressures might help to better define patients who might benefit most from stent placement. OBJECTIVE: To compare, in a retrospective cohort study, intracranial venous pressures measured under conscious (CS) sedation versus general anesthesia (GA) and to assess the relationship between anesthetic-dependent venous pressures and outcomes after VSS. METHODS: We performed a retrospective review of a prospectively maintained database to identify patients undergoing angiographic evaluation and VSS for intracranial venous stenosis. Mean venous pressures (MVPs) and trans-stenosis pressure gradients obtained under CS were compared with those measured under GA. RESULTS: The maximal MVP was significantly lower under GA (19.8 mm Hg) than CS (21.9 mm Hg; p=0.029). The MVPs in the superior sagittal sinus, torcula, and transverse sinus were lower under GA, but were significantly higher in the sigmoid sinus and jugular bulb under GA (p<0.001). The mean trans-stenosis pressure gradient was also significantly lower under GA (8.6 mm Hg) than CS (12.1 mm Hg; p<0.001). Patients with a larger difference between maximum MVP under GA versus CS were more likely to have normalization of the MVP after VSS (p=0.0008). CONCLUSIONS: Intracranial venous pressures are markedly affected by GA. In order to obtain an accurate measurement of MVPs and trans-stenosis gradients, patients undergoing investigation for IIH should undergo cerebral angiography and venous manometry under CS, which provides more reliable data for outcomes after VSS.

Comparison of different MR venography techniques for detecting transverse sinus stenosis in idiopathic intracranial hypertension.

Cerebral venous outflow abnormalities, as transverse sinuses (TSs) stenosis,may underlie a picture of idiopathic intracranial hypertension (IIH). To identify the best non-invasive MR venography (MRV) technique for exploring the disturbance of flow of TSs in IIH patients, we compared three dimensional phase contrast (3-DPC) MRV images, acquired with different velocity encodings (15 and 40 cm/s) with two-dimensional time-of-flight (2D-TOF) MR images in 6 subjects with IIH and 12 age-matched normal controls. In both groups, we also measured flow velocity in TSs by using single slice 2D-CINE PC acquisitions. In all subjects with IIH, 3D-PC showed marked flow disturbance in the mid-lateral portion of both TSs when velocity encoding (VENC) was set to 15 cm/s while only a slightly irregular flow in TSs was detected when VENC was set to 40 cm/s or when 2D-TOF was used. By contrast, 3D-PC (VENC 15 and 40) and 2D-TOF techniques were comparable in detecting TS signal flow in normal controls. Measures of flow velocity, by using 2D-CINE PC, revealed a three-fold increase of velocity at the level of the flow disturbance in IIH patients compared to normal controls (p<0.0001), suggesting a marked stenosis of mid-lateral portion of TSs in these patients. Setting the VENC to 15 cm/s on 3D-PC MRV may represent the best technical approach for visualizing disturbances of flow in TSs in subjects with symptoms suggestive of IIH.

Method for measuring sinus and vein pressure during surgery: technical note.

BACKGROUND: Measurement of dural sinus or drainage vein pressure is useful for determining the appropriate treatment for some patients. We report a novel measurement procedure that reduces bleeding from the needle puncture site as well as further tearing of the wall. METHODS: The vessel is punctured through the patch by gelatin sponge with fibrin sealant and a siliconized elastic needle is introduced. After obtaining the desired measurements, the needle is withdrawn through the fibrin sealant-bearing patch whose presence facilitates sealing of the puncture site. To further decrease the incidence of complications due to incomplete hemostasis, an additional identically prepared path is placed over the site. RESULTS: We have used this method in several operations and have encountered no complications. Our method also makes it possible to safely approach the drainers of pial arteriovenous malformations. CONCLUSIONS: Our method is easy and convenient and prevents the leakage of blood from the puncture site and further tearing of the venous wall.

An ultrasonic Doppler venous outflow method for the continuous measurement of cerebral blood flow in conscious sheep.

A pulsed ultrasonic Doppler venous outflow method was developed for the continuous measurement of global cerebral blood flow (CBF) in conscious sheep. The sheep were prepared under anesthesia with a "suture down"-style ultrasonic flow probe on the dorsal sagittal sinus placed via a trephine hole. Angiographic and dye studies showed that the dorsal sagittal sinus at the point of placement of the probe collected the majority of the blood from the cerebral hemispheres. Studies of the blood velocity profile across the sinus showed that the dimensions of the dorsal sagittal sinus changed minimally with changes in CBF in vivo. The velocity measurements were calibrated under anesthesia against an in vivo direct venous outflow method. Control CBF values for six sheep ranged from 31 to 53 ml/min for the area of brain described above; for two sheep in which the weight of the brain was determined, this gave total CBF values of approximately 34 and 30 ml min-1 100 g-1. The CBF measured varied in the expected manner with changes in the end-tidal CO2 concentration in expired breath and showed transient reductions with the barbiturate thiopentone and transient increases with the opiate alfentanil. It is concluded that the method is simple and accurate.

Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine?

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the serotonin (5HT)1B/D-like agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-sensitive structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. In this study we determined the effect of intravenous administration of the novel anti-migraine compound zolmitriptan (311C90) upon evoked neuronal activity in trigeminal neurons. Nine adult cats were anaesthetised with alpha-chloralose (60 mg/kg, i.p.; 20 mg/kg, i.v., 2-hourly) with all surgery being conducted under halothane (1-3%). The superior sagittal sinus was isolated for electrical stimulation. Recordings were made from caudal trigeminal neurons at the C2 level of the cervical spinal cord with tungsten-in-glass microelectrodes. Signals were amplified and analysed by a custom-written program that enabled software filtering and extraction of both evoked potential and single cell data. Data were collected before and after administration of zolmitriptan. Electrical stimulation of the superior sagittal sinus resulted in activation of neuronal elements within the trigeminal nucleus that could be monitored as single unit activity or as evoked potentials, the latter reflecting both primary afferent and trigeminal cell body activity. The evoked potential recorded from the trigeminal nucleus was 207 +/- 14 microV and was reduced by zolmitriptan (100 micrograms/kg, i.v.) to a mean of 98 +/- 17 microV. Similarly, the probability of firing for trigeminal neurons was reduced from a control level of 0.63 +/- 0.1 to 0.13 +/- 0.05 after a dose of 100 micrograms/kg intravenously. These effects were dose-dependent and were significantly different from the effect of vehicle (P < 0.05). These data demonstrate that systemically administered zolmitriptan can inhibit evoked trigeminovascular activity within the trigeminal nucleus. This inhibition of trigeminal activity may play a role in the anti-migraine actions of this compound and offers the prospect of a third pathophysiologically consistent target site for anti-migraine drug effects.

4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT(1B/1D) receptor agonist activity?

Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT(1B/1D)-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 microg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78+/-4 pmol/l compared to a post-4991W93 level of 79+/-3 pmol/l (n=4). In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.