NMDA/NR2B Selective Antagonists in the Treatment of Ischemic Brain Injury

Abstract

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtype-selective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…The NMDA receptor is strongly implicated in this acute neurotoxicity, and NMDA receptor antagonists targeted at the glutamate binding site, the glycine binding site, the channel pore, and an allosteric site on the GluN2B subunit are all neuroprotective in multiple preclinical models (Green, 2002;Parsons et al, 2002;Lo et al, 2003;Hoyte et al, 2004;Small and Tauskela, 2005;Wang and Shuaib, 2005;Muir, 2006). These data supported the clinical investigation for utility in preventing death and long term disability after stroke and TBI in man.…”

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

“…15 However, although glutamate-induced excitotoxicity is a crucial component of the initial ischemic insult, all tested antiglutamatergic drugs have failed in clinical trials. 2 One of the reasons for this failure might be the rapid and early Figure 2. CTX reperfusion group showed the reduced initial neurological deficit and the enhanced functional recovery over a 5-week period (A).…”

“…C ell death after cerebral ischemic insult can be induced in 3 ways: (1) by excitation (excitotoxicity), (2) by oxidative stress with free radicals, and (3) by apoptosis. 1 When the brain fails to generate sufficient ATP and this results in energy failure, ionic gradients are lost.…”

“…1 Thus, a number of NMDA receptor antagonists have been developed and used for the treatment of neurological diseases in patients, but all have failed clinical trials because of intolerable side effects or a lack of medical efficacy. 2 Glutamate transporters play a crucial role in removing glutamate released from synaptic clefts. 3 Released glutamate is taken up by glial cells and metabolized to glutamine, which is then transported back into neurons, converted to glutamate, and sequestered into synaptic vesicles by vesicular glutamate transporters.…”

Control of Assembly and Function of Glutamate Receptors by the Amino-Terminal Domain

“…After this finding, ifenprodil has been used in an exceptionally wide range of studies to explore the role of GluN2B-containing NMDA receptors in development, normal brain function, and disease (reviewed by Mony et al, 2009a). These studies have identified a wide range of normal processes and neurological diseases that involve GluN2B receptors (Wang and Shuaib, 2005;Mony et al, 2009a;Traynelis et al, 2010) and have stimulated a vigorous medicinal chemistry effort that has led to the identification of a large family of diverse organic molecules that can selectively inhibit GluN2B receptors (Table 1 and Fig. 5).…”