Protective Effect of Ifenprodil Against Spreading Depression in the Mouse Entorhinal Cortex

Abstract

Faria, Leonardo Coutinho and Istvan Mody. Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex. J Neurophysiol 92: 2610 -2614, 2004. First published June 16, 2004 10.1152/jn.00466.2004. In the brain, spreading depression (SD) is characterized by a large extracellular DC shift, a massive failure of ion homeostasis and a transient cessation of neuronal function. Clinically, SD is believed to be involved in various neurological disorders including migraine and cerebrovascular diseases. The propagation of cortical SD requires the release of glutamate, and N-methyl-D-aspartate (NMDA) receptors play a crucial role in this process. Here, we have isolated the NMDA receptor-mediated component of extracellularly recorded field excitatory postsynaptic potentials (fEPSPs) in layers 2-3 of the entorhinal cortex of murine brain slices. In the absence of GABA A and AMPA receptor-mediated synaptic transmission, stimulation of layer 6 afferents every 15-90 s elicited spontaneous SD on average within 18.5 min after the start of the stimulation. In the presence of ifenprodil, an NR2B receptor subunit-selective NMDA receptor antagonist, the occurrence of SD was nearly abolished. Our results are consistent with an important role of NR2B subunits in triggering SD in the entorhinal cortex.

Effects of Pan- and Subtype-SelectiveN-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

“…That Menniti et al (2000) blocked SD completely with CP-101,606, whereas the blockade we observed was incomplete, may be due to the precise methods of SD initiation. Our results also complement literature findings with the NR2B-selective antagonist ifenprodil in spontaneous SD generated in mouse entorhinal cortex slice preparations (Faria and Mody, 2004). Given the significant brain concentrations achieved, as discussed above, why do memantine, CP-101,606, and Ro 25-6981 not block SD completely?…”

“…Since Marrannes et al (1988) confirmed that NMDA-R is an important component in the generation and propagation of SD and associated inward currents, a variety of NMDA-R antagonists have been shown to block cortical SD (Marrannes et al, 1988;Lauritzen and Hansen, 1992;Anderson and Andrew, 2002). The role of NMDA [but not kainate or AMPA (␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors] in SD is suggested by the abilities of MK-801 (dizocilpine) and SKF-10047 (noncompetitive NMDA-R ion channel blockers) (Willette et al, 1994) and L-701,324 and ZD9379 (antagonists of the glycine site of the NMDA-R complex) (Obrenovitch and Zilkha, 1996;Tatlisumak et al, 1998), and CP-101,606 (traxoprodil) and ifenprodil (NR2B subunit-selective antagonists) (Menniti et al, 2000;Faria and Mody, 2004) to inhibit SD initiation and propagation.…”

Involvement of NMDA receptor subtypes in cortical spreading depression in rats assessed by fMRI

“…However, in brain slices of mouse entorhinal cortex, the NR2B specific antagonist ifenprodil prevented CSDs from occurring (Faria and Mody, 2004). In our experiments, NR2A antagonist TCN-201 was not effective, as it did not influence the CSD BOLD response shape.…”

Suppression of spreading depolarization and stabilization of dendritic spines by GLYX-13, an NMDA receptor glycine-site functional partial agonist

“…In this study, we found that induction of SD in rat hippocampal slices in vitro by focal elevation of [K + ] o results in a similar pattern of spine shrinkage and retraction, followed by recovery of spines once the wave of depolarization has passed and membrane potential recovers, consist with findings in neocortex of Takano et al (2007). NMDA glutamate receptor (NMDAR) activation can promote, or even be essential for, the phenomenon of SD in many experimental situations (Anderson and Andrew, 2002;Faria and Mody, 2004;Gill et al, 1992;Hartings et al, 2003;Peeters et al, 2007). NMDAR blockers such as ketamine can, at least temporarily, block SD (Amemori and Bures, 1990;Hernandez-Caceres et al, 1987;IIjima et al, 1992;Lauritzen and Hansen, 1992).…”

“…Previous studies have suggested that activation of NMDARs can be an important contributor to the generation and propagation of SD (Anderson and Andrew, 2002;Faria and Mody, 2004;Gill et al, 1992;Hartings et al, 2003;Peeters et al, 2007), and that NR2B subunit-containing NMDARs may be particularly involved under some conditions (Faria and Mody, 2004). At the same time, stimuli such as stroke (Murphy et al, 2008), oxygen/glucose deprivation (Jourdain et al, 2002) and NMDAR-dependent LTD of synaptic strength (Zhou et al, 2004), can trigger persistent shrinkage of dendritic spines in hippocampus that can be either completely, or partially, reversible.…”