No abstract

Two different topographies might be considered among IVC: strict and non-strict intraventricular location. Non-strictly IVC have wider and tighter adhesions to third ventricle boundaries and this subtype is associated with a worse outcome.

The N-methyl-D-aspartate receptor (NMDAR) is central to physiological and pathological functioning of neurons. Although promising results are beginning to be obtained in the treatment of dementias, clinical trials with NMDAR antagonists for stroke, trauma and neurodegenerative disorders, such as Hungtinton's disease, have failed before. In order to design effective therapies to prevent excitotoxic neuronal death, it is critical to characterize the consequences of excessive NMDAR activation on its expression and function. Previous data have reported partial downregulation of the NR1 and NR2B receptor subunits in response to excitotoxicity and cerebral ischemia. However, the effect of NMDAR overactivation on NR2A, a subunit fundamental to synaptic transmission and neuronal survival, is still elusive. In this study, we report the rapid and extensive proteolytic processing of NR2A, together with the scaffolding protein postsynaptic density-95 (PSD-95), induced by excitotoxic stimulation of cortical neurons in vitro and by transient focal cerebral ischemia. Processing of the C terminus of NR2A is irreversibly induced by brief agonist exposure of NR2B-containing receptors, and requires calcium influx and the activity of calpain, also responsible for PSD-95 cleavage. The outcome is a truncated NR2A subunit that is stable and capable to interact with NR1 at the surface of neurons, but lacking the structural domains required for association with scaffolding, downstream signaling and cytoskeletal proteins. Therefore, a rapid and significant uncoupling of synaptic NMDARs from downstream survival pathways is expected to occur during ischemia. This novel mechanism induced by excitotoxicity helps to explain the failure of most therapies based on NMDAR antagonists.

We investigate the profile of choline metabolites and the expression of the genes of the Kennedy pathway in biopsies of human gliomas (n = 23) using 1H High Resolution Magic Angle Spinning (HR‐MAS, 11.7 Tesla, 277 K, 4000 Hz) and individual genetic assays. 1H HR‐MAS spectra allowed the resolution and relative quantification by the LCModel of the resonances from choline (Cho), phosphocholine (PC) and glycerophosphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H NMR spectroscopy. All glioma biopsies depicted a prominent tCho peak. However, the relative contributions of Cho, PC, and GPC to tCho were different for low and high grade gliomas. Whereas GPC is the main component in low grade gliomas, the high grade gliomas show a dominant contribution of PC. This circumstance allowed the discrimination of high and low grade gliomas by 1H HR‐MAS, a result that could not be obtained using the tCho/Cr ratio commonly used by in vivo 1H NMR spectroscopy. The expression of the genes involved in choline metabolism has been investigated in the same biopsies. High grade gliomas depict an upregulation of the β gene of choline kinase and phospholipase C, as well as a downregulation of the cytidyltransferase B gene, the balance of these being consistent with the accumulation of PC. In the low grade gliomas, phospholipase A1 and lysophospholypase are upregulated and phospholipase D is downregulated, supporting the accumulation of GPC. The present findings offer a promising procedure that will potentially help to accurately grade glioma tumors using 1H HR‐MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low grade gliomas. Copyright © 2009 John Wiley & Sons, Ltd.

The N-methyl-D-aspartate (NMDA) type of glutamate receptor (NMDAR) plays central roles in normal and pathological neuronal functioning. We have examined the regulation of the NR1 subunit of the NMDAR in response to excessive activation of this receptor in in vitro and in vivo models of excitotoxicity. NR1 protein expression in cultured cortical neurons was specifically reduced by stimulation with 100 M NMDA or glutamate. NMDA decreased NR1 protein amounts by 71% after 8 h. Low NMDA concentrations (<10 M) had no effect. NR1 down-regulation was inhibited by the general NMDAR antagonist DL-AP5 and also by ifenprodil, which specifically antagonizes NMDARs containing NR2B subunits. Arrest of NMDAR signaling with DL-AP5 after brief exposure to NMDA did not prevent subsequent NR1 decrease. Down-regulation of NR1 did not involve calpain cleavage but resulted from a decrease in de novo synthesis consequence of reduced mRNA amounts. In contrast, NMDA did not alter the expression of NR2A mRNA or newly synthesized protein. In neurons transiently transfected with an NR1 promoter/luciferase reporter construct, promoter activity was reduced by 68% after 2 h of stimulation with NMDA, and its inhibition required extracellular calcium. A similar mechanism of autoregulation of the receptor probably operates during cerebral ischemia, because NR1 mRNA and protein were strongly decreased at early stages of blood reperfusion in the infarcted brains of rats subjected to occlusion of the middle cerebral artery. Because NR1 is the obligatory subunit of NMDARs, this regulatory mechanism will be fundamental to NMDAR functioning.5 type of glutamate receptor (NMDAR) plays key roles in neuronal plasticity, learning, and memory in the central nervous system, most of which are related to its high permeability to Ca 2ϩ (1). However, excessive activation of NMDARs induces excitotoxic cell death and contributes to neuronal degeneration in hypoxia, ischemia, and several neurodegenerative pathologies (2). Functional NMDARs are hetero-oligomeric proteins composed of an obligatory NR1 subunit (3-7) and NR2 subunits, denoted A-D (3,4,8,9). It is these NR2 subunits that confer functional variability to the receptor. In the post-synaptic membrane, NMDARs form large and dynamic signaling complexes by association with additional proteins (10), although there are also extrasynaptic NMDARs, which trigger different responses (11).NMDARs are subjected to multiple levels of regulation, affecting subunit expression, subcellular location, and the assembly of functional receptors and their signaling complexes (12-17). The NR1 gene is expressed in virtually all neurons, whereas NR2 transcripts display developmental and regional patterns (5, 18). The NR1 gene is transcriptionally up-regulated during neuronal differentiation, mostly by promoter de-repression (19), although positive mechanisms are also required. Post-transcriptional mechanisms also contribute to NR1 regulation in brain development, and two pools of mRNA, with different translational activities, have b...