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Background: Varied responses to acute migraine medications have been observed, with over one-third (34.5%) of patients reporting insufficient headache relief. Sumatriptan-naproxen sodium, a single, fixed-dose combination tablet comprising sumatriptan 85 mg and naproxen sodium 500 mg, was developed with the rationale of targeting multiple putative mechanisms involved in the pathogenesis of migraine to optimise acute migraine care., Methods: A narrative review of clinical trials investigating sumatriptan-naproxen sodium for both adults and adolescents was performed in March 2024., Results: Across a total of 14 clinical trials in nine publications, sumatriptan-naproxen sodium offered greater efficacy for 2-h pain freedom (14/14) and sustained pain-free response up to 24 h (13/14) compared with monotherapy and/or placebo for both adult and adolescent study participants with an acceptable and well-tolerated adverse effect profile. Clinical trial data also demonstrates the effectiveness of sumatriptan-naproxen sodium in participants with allodynia, probable migraine, menstrual-related migraine and those with poor responses to acute, non-specific, migraine medication., Conclusions: Multi-mechanistic therapeutic agents offer an opportunity to optimise acute medications by targeting multiple mediators involved in the pathogenesis of migraine. Sumatriptan-naproxen sodium resulted in greater initial and sustained pain freedom, compared with either sumatriptan, naproxen-sodium and/or placebo, for the treatment of single or multiple attacks of migraine across both adult and adolescent study populations., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is a rare, but increasingly recognised cerebrovascular condition with an estimated annual age-standardised incidence of approximately three cases per million. Knowledge about risk factors and triggering conditions and information about prognosis and optimal treatment in these patients are limited., Methods: The REversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) project aims to elucidate the epidemiological and clinical characteristics of RCVS by collecting individual patient data from four countries (France, Italy, Taiwan and South Korea) in the setting of a multicentric study. All patients with a diagnosis of definite RCVS will be included. Data on the distribution of risk factors and triggering conditions, imaging data, neurological complications, functional outcome, risk of recurrent vascular events and death and finally the use of specific treatments will be collected. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and geographical region of residence., Ethics and Dissemination: Ethical approval for the REVERCE study will be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of clinical and epidemiological characteristics of RCVS patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors do not have any conflicts of interest related to the submitted work. KSL reports personal fees (Teva, Acticor Biotech). JM reports personal fees (Abbvie, GEP Sante, Lundbeck, Homeperf, Teva, Lilly, Lundbeck, Pfizer). MJL reports personal fees (Eli Lilly, Lundbeck, Pfizer, NuEyne Co., Teva, Abbvie, SK chemical, CKD Pharm, YuYu Pharma), research grants (Eli Lilly, Otsuka, Novartis, Allergan, BioHaven, Lundbeck, Eli Lilly/Ildong), and funding Seoul National University New Faculty Startup Fund, National Research Foundation of Korea grant funded by the Korea Government (MSIP) Yuhan company). AD reports personal fees (Allergan Abbvie, Lilly, Teva, Lundbeck, Pfizer, SOS). SJW reports personal fees (AbbVie, Pfizer, Eli Lilly, Biogen), research grants (Eli Lilly, Novartis) and has been principal investigator in sponsored trials (Novartis, Lundbeck and Orient Europharma). The other authors have nothing to disclose.

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) has a heterogenous clinical and radiological presentation. We investigated whether RCVS complications vary according to age., Patients and Methods: In a pooled French cohort of 345 patients with RCVS, we assessed (1) rates of clinical and radiological complications, and (2) the functional outcome at 3 months according to age as a continuous variable, and in young patients aged ≤ 49 years versus those aged ≥ 50 years. The Commission Nationale Informatique et Liberté and the local ethics committee approved this study (registration number: 202100733)., Results: The risk for any focal deficit and for any brain lesion were independently associated with increasing age (OR 1.4, 95% CI 1.1-1.8; p = 0.014, and OR 1.6, 95% CI 1.2-2.1; p < 0.001, respectively). Subtypes of brain lesions independently associated with increasing age were subarachnoid haemorrhage (OR 1.7, 95% CI 1.3-2.3; p < 0.001) and intracerebral haemorrhage (OR 1.5, 95% CI 1.1-2.2; p = 0.023). Frequency of cervical artery dissections peaked at age 30-39, and young age was independently associated with cervical artery dissections (OR 13.6, 95% CI 2.4-76.6; p = 0.003). Age had no impact on the functional outcome, with a modified Rankin scale score of 0-1 in > 96% of patients., Conclusion: Age seems to influence rates and types of complications of RCVS, with young age being associated with cervical artery dissections, and increasing age with haemorrhagic complications. If confirmed in larger prospective studies, recognition of age-specific patterns might help to guide clinical management and to identify complications in cases of RCVS and vice versa., (© 2023. The Author(s).)

Background: The diagnosis of cervicogenic headache (CGH) remains a challenge for clinicians as the diagnostic value of detailed history and clinical findings remains unclear., Objectives: To update and evaluate available evidence of the prevalence and the diagnostic accuracy of the detailed history and clinical findings for CGH in adults with headache., Design: Systematic review with meta-analysis., Methods: CINAHL, Cochrane Central, Embase, PEDro and PubMed were searched for studies before March 2022 that reported detailed history and/or clinical findings related to the diagnosis of cervicogenic headache. Study selection, risk of bias assessment (QUADAS-2 and PROBAST), and data extraction were performed. Meta-analyses for the cervical flexion-rotation test (CFRT) was performed. Certainty of the evidence was assessed with the GRADE approach., Results: Eleven studies were included. Moderate certainty evidence indicated that the CFRT differentiated CGH from lower cervical facet-induced headache, migraine, concomitant headaches or asymptomatic subjects (Se 83.0% [95%CI:70.0%-92.0%]; Sp 83.0% [95%CI:71.0%-91.0%]; positive LR 5.0 [95%CI:2.6-9.5]; negative LR 0.2 [95%CI:0.1-0.4]; n = 4 studies; n = 182 participants). Several diagnostic classifications and test clusters based on headache history and clinical findings can be useful, despite uncertain accuracy, in formulating the diagnosis of CGH., Conclusion: Evidence support to undertake an evaluation of headache history and signs and symptoms and a physical examination of the patient neck to diagnose CGH. During the physical examination, a positive or negative CFRT probably has a small to moderate effect on the probability of a patient having a CGH. The diagnostic value of the other findings remains unclear., Trial Registration: #CRD42020201772., Competing Interests: Declaration of competing interest JM received travel, accommodation, and meeting expenses from SOS oxygen, AMGEN, Novartis and Homeperf and received honoraria for advisory boards or symposium from Lilly, Teva, and Novartis not related to the submitted work. AD, SL and LB declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In a recent Italian study, 30% of patients with reversible cerebral vasoconstriction syndrome (RCVS) presented without thunderclap headache (TCH), and tended to present more severe forms of RCVS than patients with TCH. We aimed to analyze the risk for complications of RCVS in patients with and without TCH at onset., Methods: In a pooled cohort of 345 French patients with RCVS, we compared patients with and without TCH at onset regarding rates of neurological complications, and the functional outcome at 3 months., Results: As compared to the 281 patients with TCH at onset, the 64 patients without TCH had a higher risk for any neurological complication (61% vs. 24%, OR 4.9, 95% CI 2.8-8.7, p < 0.001). The association was strongest for cervical artery dissections (28% vs. 5%, OR 8.1, 95% CI 3.7-17.6, p < 0.001), followed by posterior reversible encephalopathy syndrome (17% vs. 3%, OR 7.1, 95% CI 2.7-18.4, p < 0.001), seizures (9% vs. 2.5%, OR 4.1, 95% CI 1.3-12.5, p = 0.019), and subarachnoid hemorrhage (41% vs. 16%, OR 3.5, 95% CI 1.9-6.3, p < 0.001). In multivariable analysis, the risk for any neurological complication remained significantly elevated in the absence of TCH (OR 3.5, 95% CI 1.8-6.8, p < 0.001). The functional outcome was equal in both groups, with a modified Rankin scale score of 0-1 in ≥90% of patients., Conclusions: Absence of TCH at onset might predict a higher risk of complications in RCVS. Our results warrant further multicentric studies to prove this finding., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Several neuromodulation methods exists for migraine treatment. The aim of the present study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on migraine treatment using neurostimulation methods., Methods: We searched Medline and Embase up to July 1, 2020 for RCTs reporting acute or preventive treatment of migraine with either non-invasive or invasive neurostimulation methods. Two researchers independently assessed the eligibility of the retrieved studies and extracted data. Outcomes for the quantitative synthesis were 2 h pain free for acute treatment and headache days per month for preventive treatment. We performed subgroup analyses by treatment (stimulation method and site of application). Estimates were pooled using random-effects meta-analysis., Results: Thirty-eight articles were included in the qualitative analysis (7 acute, 31 preventive) and 34 in the quantitative evaluation (6 acute, 28 preventive). Remote electrical neuromodulation (REN) was effective for acute treatment. Data were insufficient to draw conclusions for any other techniques (single studies). Invasive occipital nerve stimulation (ONS) was effective for migraine prevention, with a large effect size but considerable heterogeneity, whereas supra-orbital transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), and high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) were effective, with small to medium effect sizes. Vagus-nerve stimulation, left prefrontal cortex rTMS, and cathodal transcranial direct current stimulation (tDCS) over the M1 had no significant effect and heterogeneity was high., Conclusion: Several neuromodulation methods are of potential interest for migraine management, but the quality of the evidence is very poor. Future large and well-conducted studies are needed and could improve on the present results.

Background and Purpose- We aimed to further investigate the long-term outcomes after reversible cerebral vasoconstriction syndrome (RCVS). Methods- A longitudinal follow-up study was conducted in 173 RCVS patients. Results- Of the 172 patients who completed a mean follow-up of 9.2±3.3 years, 10 had a recurrent RCVS that was benign in all. Independent predictors of relapse were having a history of migraine and having exercise as a trigger for thunderclap headache during initial RCVS. After new delivery, the rate of postpartum RCVS was 9%. Conclusions- Overall, long-term outcome after RCVS is excellent.

Stroke-prone spontaneously hypertensive rats (SHRSP) on high-salt diet are characterized by extremely high arterial pressures, and have been endorsed as a model for hypertensive small vessel disease and vascular cognitive impairment. However, rapidly developing malignant hypertension is a well-known cause of posterior reversible encephalopathy syndrome (PRES) in humans, associated with acute neurological deficits, seizures, vasogenic cerebral edema and microhemorrhages. In this study, we aimed to examine the overlap between human PRES and SHRSP on high-salt diet. In SHRSP, arterial blood pressure progressively increased after the onset of high-salt diet and seizure-like signs emerged within three to five weeks. MRI revealed progressive T2-hyperintense lesions suggestive of vasogenic edema predominantly in the cortical watershed and white matter regions. Histopathology confirmed severe blood-brain barrier disruption, white matter vacuolization and microbleeds that were more severe posteriorly. Hematological data suggested a thrombotic microangiopathy as a potential underlying mechanism. Unilateral common carotid artery occlusion protected the ipsilateral hemisphere from neuropathological abnormalities. Notably, all MRI and histopathological abnormalities were acutely reversible upon switching to regular diet and starting antihypertensive treatment. Altogether our data suggest that SHRSP on high-salt diet recapitulates the neurological, histopathological and imaging features of human PRES rather than chronic progressive small vessel disease.

Objectives: To further improve the distinction between primary angiitis of the CNS (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS)., Methods: We compared 2 large French cohorts of patients with PACNS (n = 110, retrospectively and prospectively enrolled) and RCVS (n = 173, prospectively enrolled)., Results: Patients with RCVS were predominantly female ( p < 0.0001), with migraines ( p < 0.0001), and were more often exposed to vasoactive substances ( p < 0.0001) or postpartum ( p = 0.002) than patients with PACNS. Headache, especially thunderclap headache, was more frequent in RCVS (both p < 0.0001). Thunderclap headache was absent in only 6% of patients with RCVS and was mainly recurrent (87%) and provoked (77%) mostly by sexual intercourse, exertion, or emotion. All other neurologic symptoms (motor deficit, seizure, cognitive disorder, or vigilance impairment, all p < 0.0001) were more frequent in PACNS. At admission, brain CT or MRI was abnormal in all patients with PACNS and in 31% of patients with RCVS ( p < 0.0001). Acute ischemic stroke was more frequent in PACNS than in RCVS ( p < 0.0001). Although intracerebral hemorrhage was more frequent in PACNS ( p = 0.006), subarachnoid hemorrhage and vasogenic edema predominated in RCVS ( p = 0.04 and p = 0.01, respectively). Multiple small deep infarcts, extensive deep white matter lesions, tumor-like lesions, or multiple gadolinium-enhanced lesions were observed only in PACNS, whereas cervical artery dissection was found only in RCVS., Conclusions: Our study confirms that careful analysis of clinical context, headache features, and patterns of brain lesions can distinguish PACNS and RCVS within the first few days of admission in most cases. However, diagnosis remains challenging in a few cases., (© 2018 American Academy of Neurology.)

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

We identified and characterized a series of pyrrole amides as potent, selective Ca v 3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Ca v 3.1- and Ca v 3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.

Background and objective Migraine with aura (MA) is a major symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We assessed the spectrum of migraine symptoms and their potential correlates in a large prospective cohort of CADASIL individuals. Methods A standardized questionnaire was used in 378 CADASIL patients for assessing headache symptoms, trigger factors, age at first attack, frequency of attacks and associated symptoms. MRI lesions and brain atrophy were quantified. Results A total of 54.5% of individuals had a history of migraine, mostly MA in 84% of them; 62.4% of individuals with MA were women and age at onset of MA was lower in women than in men. Atypical aura symptoms were experienced by 59.3% of individuals with MA, and for 19.7% of patients with MA the aura was never accompanied by headache. MA was the inaugural manifestation in 41% of symptomatic patients and an isolated symptom in 12.1% of individuals. Slightly higher MMSE and MDRS scores and lower Rankin score were detected in the MA group. Conclusion MA is observed in almost half of all CADASIL patients. Atypical aura symptoms are reported by more than one in two of them. MA is often inaugural, can remain isolated and is not associated with the severity of the disorder.

Headache is the common thread of migraine, reversible cerebral vasoconstriction syndrome (RCVS) and cervical artery dissection (CeAD), three medical conditions that otherwise appear to be very different. However, epidemiological, clinical and genetic data suggest that these conditions share common and complex features and are, at least partly, linked. The purpose of this manuscript is to review existing evidence for an association between migraine, RCVS and CeAD and discuss the potential underlying mechanisms., (© 2016 American Headache Society.)

Objective: Migraine, particularly with aura, is a risk factor for ischemic stroke. Recent data in migraine mutant mice suggest that cerebral hyperexcitability associated with migraine accelerates recruitment of ischemic penumbra into the core, resulting in faster infarct growth compared with wild type. We hypothesized that individuals with a history of migraine are more likely to exhibit increased recruitment of ischemic tissue into the infarct in acute stroke., Methods: In this retrospective case-control study, we identified participants with reliably documented migraine history, measured lesion volumes on diffusion-weighted and perfusion-weighted MRI obtained within 72 hours of symptom onset, calculated the proportion of ischemic tissue on perfusion-weighted imaging (PWI) hyperintense on diffusion-weighted imaging (DWI), and compared the proportion of patients with no-mismatch pattern defined as DWI lesion >83% of PWI lesion., Results: Migraineurs (n = 45) were younger, more often female, less likely to have vascular risk factors, and more often had cervical artery dissection, but otherwise did not differ from controls (n = 27). A significantly larger proportion of migraineurs had no-mismatch pattern, indicating that the entire perfusion defect was recruited into the infarct by the time of MRI (22% vs 4% of migraineurs and controls, respectively; p = 0.044). The difference was even more prominent in migraineurs with aura (36% vs 4%, p = 0.019). The association between migraine and no-mismatch pattern persisted after adjustment for time to MRI (p = 0.041)., Conclusions: This case-control study supports the hypothesis that a history of migraine, particularly with aura, is associated with a no-mismatch pattern during acute ischemic stroke, consistent with data obtained in migraine mutant mice., (© 2015 American Academy of Neurology.)

Background: Migraine, particularly with aura, increases the risk for ischemic stroke, at least in a subset of patients. The underlying mechanisms are poorly understood and probably multifactorial., Methods: We carried out an extended literature review of experimental and clinical evidence supporting the association between migraine and ischemic stroke to identify potential mechanisms that can explain the association., Results: Observational, imaging and genetic evidence support a link between migraine and ischemic stroke. Based on clinical and experimental data, we propose mechanistic hypotheses to explain the link, such as microembolic triggers of migraine and enhanced sensitivity to ischemic injury in migraineurs., Discussion: We discuss the possible practical implications of clinical and experimental data, such as aggressive risk factor screening and management, stroke prophylaxis and specific acute stroke management in migraineurs. However, evidence from prospective clinical trials is required before modifying the practice in this patient population., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Diffusion tensor imaging (DTI) histogram metrics are correlated with clinical parameters in cerebral small vessel diseases (cSVD). Whether ADC histogram parameters derived from simple diffusion weighted imaging (DWI) can provide relevant markers for long term studies of cSVD remains unknown. CADASIL patients were evaluated by DWI and DTI in a large cohort study over a 6-year period. ADC histogram parameters were compared to those derived from mean diffusivity (MD) histograms in 280 patients using intra-class correlation and Bland-Altman plots. Impact of image corrections applied to ADC maps was assessed and a mixed effect model was used for analyzing the effects of scanner upgrades. The results showed that ADC histogram parameters are strongly correlated to MD histogram parameters and that image corrections have only limited influence on these results. Unexpectedly, scanner upgrades were found to have major effects on diffusion measures with DWI or DTI that can be even larger than those related to patients' characteristics. These data support that ADC histograms from daily used DWI can provide relevant parameters for assessing cSVD, but the variability related to scanner upgrades as regularly performed in clinical centers should be determined precisely for longitudinal and multicentric studies using diffusion MRI in cSVD.

Contrasting with the abundant literature dedicated to atrial fibrillation (AF) and to the use of new oral anticoagulants in this setting, very few recent studies have focused on patients with AF-associated stroke. From November 2010 to March 2011, we conducted a small prospective 4-month study in the stroke units of Lariboisière and Bicêtre hospitals. Fifty patients with FA and stroke were included (14% of all strokes), including 45 patients with cerebral infarcts (CI), 3 with transient ischemic attacks (TIA) and 2 with intracerebral hemorrhage (ICH). The results of this study, together with a review of the sparse relevant literature, underline the following points: these patients tend to be older and more frequently female than in recent clinical trials; TIAs are rare; these patients have numerous vascular risk factors and associated cerebrovascular diseases such as atheroma and leukoaraiosis; CI is often extensive and hemorrhagic; AF is discovered in a stroke unit in 40% of cases and is paroxystic in 33% of cases, with no consensus on the potential regulation; there is massive underuse of VKA in patients with known AF; rtPA intravenous thrombolysis is frequent; treatment difficulties arise in patients with AF-related CI and a history of ICH; the prognosis of VKA-related ICH is poor; the use of oral anticoagulants alone or combined with aspirin is controversial in case of AF associated with severe atheroma. Patients with AF seen in stroke units are therefore very different from those seen by cardiologists: they are older and have many vascular risk factors, stroke, and other cerebrovascular lesions, raising difficult treatment issues owing to the dual risk of embolic recurrence and symptomatic hemorrhagic transformation. In addition, contraindications to long-term VKA use are frequent. Many of these issues will again be raised with the arrival of new oral anticoagulants.

Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations of the NOTCH3 gene. Marked variations in disease severity have raised the hypothesis that non-genetic factors may modulate the expressivity of the phenotype. The aim of the current study was to evaluate whether atherosclerosis, assessed by carotid duplex ultrasonography, is associated with variations in the clinical and MRI phenotype of CADASIL., Methods: Data from 144 consecutive patients enrolled in an ongoing prospective cohort study were collected. Degree of disability was assessed by the modified Rankin Scale, that of cognitive impairment by the Mattis Dementia Rating Scale (MDRS). The total volume of the brain, of lacunar lesions and of white matter hyperintensities, the number of cerebral microhemorrhages, and parameters derived from histograms of apparent diffusion coefficient were measured on cerebral MRI. Atherosclerosis was evaluated by B-mode ultrasonography of carotid arteries. Both the carotid intima-media thickness (cIMT) and the presence of carotid plaques or stenosis were recorded., Results: Higher cIMT was found to be independently associated with lower MDRS scores when this score was less than the quartile limit (p = 0.02). Only a trend for a positive association was detected between cIMT and the Rankin score (p = 0.06). There was no significant association between carotid markers and the occurrence of stroke or MRI parameters except for diffusion data. The mean and peak values of MRI diffusion histograms were found positively associated with the presence of plaques (p < 0.01)., Conclusion: The results suggest that the severity of atherosclerosis may relate to cognitive decline in CADASIL and that this effect is possibly related to the degree of microstructural cerebral tissue lesions. Longitudinal studies are needed to confirm these results., (Copyright © 2010 S. Karger AG, Basel.)

RalA and RalB constitute a family of highly similar Ras-related GTPases widely distributed in different tissues. Recently, active forms of Ral proteins have been shown to bind to the exocyst complex, implicating them in the regulation of cellular secretion. Since RalA is present on the plasma membrane in neuroendocrine chromaffin and PC12 cells, we investigated the potential role of RalA in calcium-regulated exocytotic secretion. We show here that endogenous RalA is activated during exocytosis. Expression of the constitutively active RalA (G23V) mutant enhances secretagogue-evoked secretion from PC12 cells. Conversely, expression of the constitutively inactive GDP-bound RalA (G26A) or silencing of the RalA gene by RNA interference led to a strong impairment of the exocytotic response. RalA was found to co-localize with phospholipase D1 (PLD1) at the plasma membrane in PC12 cells. We demonstrate that cell stimulation triggers a direct interaction between RalA and ARF6-activated PLD1. Moreover, reduction of endogenous RalA expression level interfered with the activation of PLD1 observed in secretagogue-stimulated cells. Finally, using various RalA mutants selectively impaired in their ability to activate downstream effectors, we show that PLD1 activation is essential for the activation of secretion by GTP-loaded RalA. Together, these results provide evidence that RalA is a positive regulator of calcium-evoked exocytosis of large dense core secretory granules and suggest that stimulation of PLD1 and consequent changes in plasma membrane phospholipid composition is the major function RalA undertakes in calcium-regulated exocytosis.