NMDA-induced currents

Effects of ethanol and crocin on NMDA-induced currents in single hippocampal neurons... 

In order to confirm the possible interaction of ethanol and crocin on NMDA receptors, we also performed whole-cell patch recording with primary cultured hippocampal neurons and measured membrane currents induced by the application of NMDA in a voltage-clamped condition. Application of 100 pM NMDA induced an inward current of 100.2 9.8 pA (n=10) at a holding potential of -60 mV. The NMDA-induced inward current was not affected by 10 pM CNQX (data not shown), but was completely abolished by 30 pM APV, supporting the fact that the response was mediated by NMDA receptors. Ethanol inhibited NMDA-induced currents in a concentration-dependent manner. Crocin (10 pM) had no effect on NMDA-induced currents by itself (data not shown), but attenuated the inhibitory effect of ethanol on NMDA-induced currents. The concentration-effect curve for ethanol was shifted to the right by the presence of crocin [22]. 

Frankiewici. T., Potier, B., Bashir. Z. 1., Collingridge. C. L, aitd Parsons, C. G. (1996). Effects of memantine and MK-801 on NMDA-indUced current.s in cultured neurones and on. synaptic transmission and LTP in area CAI of rat hippocampal slices. UkJ. Phuntiacol. 117,689-697. 

Redox phenomena seem to modulate activity of the NMDA subtype of glutamate receptors. Ascorbic acid inhibits binding of [ H]glutamate to the NMDA-receptor complex and impedes NMDA-gated currents in isolated neurons, whereas dithiothreitol-like reductants enhance NMDA-induced currents (Majewska et aL, 1990). The ability of reductants to alter function of the NMDA receptors is prevented by oxidation. This inhibitory effect of ascorbic acid on NMDA receptors may act to protect against excitotoxic insults to the neurons (Section 6). 

Klein, R,C Galdzicki, Z., and CasteHino, F,J, (1999) Inhibition of NMDA-induced currents by conantokin-G and conantokin-T in... 

Hollmann, M., Boulter, J., Maron, C Beasley, L Sullivan, J., Pecht, G., and Heinemann, S. (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10,943-954. 

Furukawa K. and Mattson M. P. (1998). The transcription factor NF-/cB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-a in hippocampal neurons. J. Neurochem. 70 1876-1886. 

Heidinger V, Manzerra P, Wang XQ, Strasser U, Yu SP, et al. 2002. Metabotropic glutamate receptor 1-induced upregu-lation of NMDA receptor current Mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neu-rosci 22 5452-5461. 

Dysbindin-1 is expressed by glutamatergic neurons and by their targets cells in brain areas affected in schizophrenia, including the DLPFC, hippocampal formation, and striatum (see Sections 2.2.6.3.2.3.4— 2.2.6.3.2.3.6). Reduced dysbindin-1 levels in such cells and their targets is likely to contribute to glutamatergic dysfunction in schizophrenia, because dysbindin-1 knockdown in cerebrocortical cells reduces stimulus-induced release of glutamate (Numakawa et al., 2004) and because dysbindin-1 loss in sdy mice leads to reduced NMDA-mediated currents in the rodent homolog of the primate DLPFC (Andrew et al.,... 

Cepeda C, Colwell CS, Itri JN, Chandler SH, Levine MS (1998) Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices contribution of calcium conductances. J Neurophysiol 79 82-94. 

Furukawa K, Mattson MP (1998) The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 70 1876-1886 Gabriel C, Justida C, Gamins A, Planas AM (1999) Activation of nucletir factor-kappaB in the rat brain after transient focal ischemia. Brain Res Mol Brain Res 65 61-69 Gary DS, Sooy K, Chan SL, Christakos S, Mattson MP (2000) Concentration- tmd cell type-specific effects of calbindin D28k on vulnerability of hippocamptil neurons to seizure-induced injury. Brain Res Mol Brain Res 75 89-95... 

P. Rossi et al.. Differential long-lasting potentiation of the NMDA and non-NMDA synaptic currents induced by metabotropic and NMDA receptor coactivation in cerebellar granule celts. Eur. J. Neurosci.. 8 (1996) 1182-1189. 

Lea PM, Custer SJ, Vicini S et al (2002) Neuronal and glial mGluR5 modulation prevents stretch-induced enhancement of NMDA receptor current. Pharmacol Biochem Behav 73 287-298... 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Type B effects vary depending on the drug used, e.g. heparin and thrombocytopenia, ticlopidine and thrombocytopenia. Clopidrogel shows excellent acceptability. According to the results of phase I and phase II trials, the neurocytoprotectors currently under development have a very variable safety profile. Anti-NMDA agents can induce psychostimulation, psychotomimetic effects and increase blood pressure. For cardiac effects, QTc lengthening is still a problem with eliprodil and lubeluzole. 

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