Laboratory of Experimental Neurology

Brussels, Belgium

Laboratory of Experimental Neurology

Brussels, Belgium
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Debette S.,Lille University Hospital Center | Debette S.,French Institute of Health and Medical Research | Debette S.,University of Versailles | Grond-Ginsbach C.,University of Heidelberg | And 20 more authors.
Neurology | Year: 2011

Objective: To examine whether risk factor profile, baseline features, and outcome of cervical artery dissection (CEAD) differ according to the dissection site. Methods: We analyzed 982 consecutive patients with CEAD included in the Cervical Artery Dissection and Ischemic Stroke Patients observational study (n = 619 with internal carotid artery dissection [ICAD], n = 327 with vertebral artery dissection [VAD], n = 36 with ICAD and VAD). Results: Patients with ICAD were older (p < 0.0001), more often men (p = 0.006), more frequently had a recent infection (odds ratio [OR] = 1.59 [95% confidence interval (CI) 1.09-2.31]), and tended to report less often a minor neck trauma in the previous month (OR=0.75 [0.56-1.007]) compared to patients with VAD. Clinically, patients with ICAD more often presented with headache at admission (OR = 1.36 [1.01-1.84]) but less frequently complained of cervical pain (OR = 0.36 [0.27-0.48]) or had cerebral ischemia (OR = 0.32 [0.21-0.49]) than patients with VAD. Among patients with CEAD who sustained an ischemic stroke, the NIH Stroke Scale (NIHSS) score at admission was higher in patients with ICAD than patients withVAD(OR=1.17 [1.12-1.22]). Aneurysmal dilatation was more common (OR = 1.80 [1.13-2.87]) and bilateral dissection less frequent (OR = 0.63 [0.42-0.95]) in patients with ICAD. Multiple concomitant dissections tended to cluster on the same artery type rather than involving both a vertebral and carotid artery. Patients with ICAD had a less favorable 3-month functional outcome (modified Rankin Scale score>2, OR=3.99 [2.32-6.88]), but this was no longer significant after adjusting for baseline NIHSS score. Conclusion: In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome. © 2011 by AAN Enterprises, Inc.


Debette S.,French Institute of Health and Medical Research | Debette S.,Lille University Hospital Center | Debette S.,University of Versailles | Metso T.,University of Helsinki | And 24 more authors.
Circulation | Year: 2011

Background: Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. Methods and Results: The study sample comprised 690 CEAD patients (mean age, 44.2±9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7±10.5 years; 39.9% women), and 1170 referents (45.9±8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥30 kg/m2) or overweightness (body mass index ≥25 kg/m2 and <30 kg/m2) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. Conclusion: These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD. © 2011 American Heart Association, Inc.


Nistico R.,EBRI Rita Levi Montalcini Foundation | Nistico R.,University of Rome La Sapienza | Florenzano F.,EBRI Rita Levi Montalcini Foundation | Mango D.,EBRI Rita Levi Montalcini Foundation | And 15 more authors.
Scientific Reports | Year: 2015

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions. © 2015, Nature Publishing Group. All rights reserved.


PubMed | Howard Hughes Medical Institute, University of Genoa, EBRI Rita Levi Montalcini Foundation, Santa Lucía University and 3 more.
Type: | Journal: Scientific reports | Year: 2015

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions.


Terrinoni A.,Biochemistry Laboratory | Codispoti A.,Biochemistry Laboratory | Serra V.,Biochemistry Laboratory | Didona B.,IDI IRCCS | And 8 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

The autosomic dominant KID Syndrome (MIM 148210), due to mutations in GJB2 (connexin 26, Cx26), is an ectodermal dysplasia with erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. The Cx26 protein is a component of gap junction channels in epithelia, including the cochlea, which coordinates the exchange of molecules and ions. Here, we demonstrate that different Cx26 mutants (Cx26D50N and Cx26G11E) cause cell death in vitro by the alteration of intra-cellular calcium concentrations. These results help to explain the pathogenesis of both the hearing and skin phenotypes, since calcium is also a potent regulator of the epidermal differentiation process. Crown Copyright © 2010.


Lemons L.L.,Laboratory of Experimental Neurology | Lemons L.L.,Vanderbilt University | Wiley R.G.,Laboratory of Experimental Neurology | Wiley R.G.,Vanderbilt University
Neuropeptides | Year: 2011

Galanin, along with enkephalins and neuropeptide Y, has been hypothesized to negatively modulate nociception in the superficial dorsal horn of the spinal cord. In the present study, we sought to determine the role of presumably excitatory dorsal horn galanin receptor-expressing neurons in nociception by selectively destroying GalR1-expressing superficial dorsal horn interneurons using lumbar intrathecal injections of the targeted cytotoxin, galanin-saporin (Gal-sap). Lumbar intrathecal injection of Gal-sap (500. ng) reduced immunoperoxidase staining for GalR1 in the superficial dorsal horn without affecting primary afferent neurons in lumbar dorsal root ganglia. Lumbar intrathecal Gal-sap also: 1 - reduced nocifensive reflex responding on the thermal plate at 0.3°C, 44°C, and 47°C; 2 - increased hot side occupancy in a thermal preference task (15°C vs 45°C); and, 3 - decreased escape from 44°C and 47°C, but not 20°C. Thus, similar to lesions of mu opiate receptor-expressing dorsal horn interneurons, selective destruction of GalR1-expressing superficial dorsal horn neurons produces heat hypo-algesia, likely due to loss of GalR1-expressing excitatory interneurons leading to reduced activation of nociceptive projection neurons in response to aversive heat. These results are different than those seen with intrathecal neuropeptide Y-saporin and suggest the potential value of selectively targeting GalR1-expressing dorsal horn neurons to control pain. © 2011.


Bonito-Oliva A.,Karolinska Institutet | Pignatelli M.,University of Rome La Sapienza | Pignatelli M.,European Brain Research Institute | Spigolon G.,Karolinska Institutet | And 10 more authors.
Biological Psychiatry | Year: 2014

Background: Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway and the emergence of rigidity, tremor, and bradykinesia. Accumulating evidence indicates that PD is also accompanied by nonmotor symptoms including cognitive deficits, often manifested as impaired visuospatial memory. Methods: We studied cognitive performance and synaptic plasticity in a mouse model of PD, characterized by partial lesion of the dopaminergic and noradrenergic inputs to striatum and hippocampus. Sham- and 6-hydroxydopamine-lesioned mice were subjected to the novel object recognition test, and long-term potentiation was examined in the dentate gyrus and CA1 regions of the hippocampus. Results: Bilateral 6-hydroxydopamine lesion reduced long-term but not short-term novel object recognition and decreased long-term potentiation specifically in the dentate gyrus. These abnormalities did not depend on the loss of noradrenaline but were abolished by the antiparkinsonian drug, L-DOPA, or by SKF81297, a dopamine D1-type receptor agonist. In contrast, activation of dopamine D2-type receptors did not modify the effects produced by the lesion. Blockade of the extracellular signal-regulated kinases prevented the ability of SKF81297 to rescue novel object recognition and long-term potentiation. Conclusions: These findings show that partial dopamine depletion leads to impairment of long-term recognition memory accompanied by abnormal synaptic plasticity in the dentate gyrus. They also demonstrate that activation of dopamine D1 receptors corrects these deficits, through a mechanism that requires intact extracellular signal-regulated kinases signaling. © 2014 Society of Biological Psychiatry.


Datta S.,Vanderbilt University | Datta S.,Laboratory of Experimental Neurology | Chatterjee K.,Laboratory of Experimental Neurology | Kline IV R.H.,Laboratory of Experimental Neurology | And 2 more authors.
Molecular Pain | Year: 2010

Background: Unilateral constrictive sciatic nerve injury (uCCI) is a common neuropathic pain model. However, the bilateral constrictive injury (bCCI) model is less well studied, and shows unique characteristics. In the present study, we sought to correlate effects of bCCI on nocifensive responses to cold and mechanical stimuli with selected dorsal horn anatomic markers. bCCI or sham ligation of both rat sciatic nerves were followed up to 90 days of behavioural testing. Additional rats sacrificed at 15, 30 and 90 days were used for anatomic analyses. Behavioural tests included hindpaw withdrawal responses to topical acetone, cold plate testing, an operant thermal preference task and hindpaw withdrawal thresholds to mechanical probing.Results: All nocifensive responses to cold increased and remained enhanced for >45 days. Mechanical withdrawal thresholds decreased for 25 days only. Densitometric analyses of immunoperoxidase staining in the superficial dorsal horn at L4-5 revealed decreased cholecystokinin (CCK) staining at all times after bCCI, decreased mu opiate receptor (MOR) staining, maximal at 15 days, increased neuropeptide Y (NPY) staining only at days 15 and 30, and increased neurokinin-1 receptor (NK-1R) staining at all time points, maximal at 15 days. Correlation analyses at 45 days post-bCCI, were significant for individual rat nocifensive responses in each cold test and CCK and NK-1R, but not for MOR or NPY.Conclusions: These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain. © 2010 Datta et al; licensee BioMed Central Ltd.


Rubio-Agusti I.,Laboratory of Experimental Neurology | Perez-Miralles F.,Laboratory of Experimental Neurology | Sevilla T.,Laboratory of Experimental Neurology | Sevilla T.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | And 13 more authors.
Neurology | Year: 2011

Objective: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings. Methods: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies. Results: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8. Conclusions: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series. © 2011 by AAN Enterprises, Inc.


PubMed | Laboratory of Experimental Neurology
Type: Journal Article | Journal: British journal of pharmacology | Year: 2012

For many years after its discovery, hydrogen peroxide (HO) was viewed as a toxic molecule to human tissues; however, in light of recent findings, it is being recognized as an ubiquitous endogenous molecule of life as its biological role has been better elucidated. Indeed, increasing evidence suggests that HO may act as a second messenger with a pro-survival role in several physiological processes. In addition, our group has recently demonstrated neuroprotective effects of HO on in vitro and in vivo ischaemic models through a catalase (CAT) enzyme-mediated mechanism. Therefore, the present review summarizes experimental data supporting a neuroprotective potential of HO in ischaemic stroke that has been principally achieved by means of pharmacological and genetic strategies that modify either the activity or the expression of the superoxide dismutase (SOD), glutathione peroxidase (GPx) and CAT enzymes, which are key regulators of HO metabolism. It also critically discusses a translational impact concerning the role played by HO in ischaemic stroke. Based on these data, we hope that further research will be done in order to better understand the mechanisms underlying HO functions and to promote successful HO signalling based therapy in ischaemic stroke.

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