Distant Space Processing is Controlled by tPA-dependent NMDA Receptor Signaling in the Entorhinal Cortex

International audienceIn humans, spatial cognition and navigation impairments are a frequent situation during physiological and pathological aging, leading to a dramatic deterioration in the quality of life. Despite the discovery of neurons with location-specific activity in rodents, that is, place cells in the hippocampus and later on grid cells in the entorhinal cortex (EC), the molecular mechanisms underlying spatial cognition are still poorly known. Our present data bring together in an unusual combination 2 molecules of primary biological importance: a major neuronal excitatory receptor, N-methyl-D-aspartate receptor (NMDAR), and an extracellular protease, tissue plasminogen activator (tPA), in the control of spatial navigation. By using tPA-deficient mice and a structure-selective pharmacological approach, we demonstrate that the tPA-dependent NMDAR signaling potentiation in the EC plays a key and selective role in the encoding and the subsequent use of distant landmarks during spatial learning. We also demonstrate that this novel function of tPA in the EC is reduced during aging. Overall, these results argue for the concept that encoding of proximal versus distal landmarks is mediated not only by different anatomical pathways but also by different molecular mechanisms, with the tPA-dependent potentiation of NMDAR signaling in the EC that plays an important role

Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor

Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors

[Abstract] Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient's functional situation in the first 3 months. To compare quantitative variables, we used Student's t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient's worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2014-56336-R), Xunta de Galicia (Consellería de Educación: GRC2014/027 and Axencia Galega de Innovación), Instituto de Salud Carlos III (PI13/00292 and PI14/01879), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS (RD16/0019), European Union FEDER program. Furthermore, T. Sobrino (CP12/03121) and F. Campos (CP14/00154) are recipients of research contracts (Miguel Servet Program of Instituto de Salud Carlos III). Clara Correa-Paz is the recipient of an FPI fellowship (BES-2015-073933) Spanish Ministry of Economy and Competitiveness.info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/SAF2014-56336-R/ES/NANONEUROPROTECCION TERMO-MOLECULAR VECTORIZADA EN LA ISQUEMIA CEREBRALXunta de Galicia; GRC2014/027info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/PI13%2F00292/ES/Encapsulación del activador del plasminógeno tisular (tPA) en nanoestructuras vectorizadas y eco-sensiblesinfo:eu-repo/grantAgremeent/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/PI14%2F01879/ES/Reprogramación in vivo del cerebro isquémico como nueva opción terapéutica en el infarto cerebralinfo:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/RD16%2F0019%2F0015/ES/Red de Enfermedades Vasculares Cerebrales. INVICTUS PLUSinfo:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/CP14%2F00154/ES/info:eu-repo/grantAgreement/MINECO/Programa Estatal de Promoción del Talento y su Empleabilidad/BES-2015-073933/ES