cp-101-606 and Brain-Ischemia

Over the past decade, there have been major advances in our understanding of the role of glutamate and N-methyl-d-aspartate (NMDA) receptors in several disorders of the central nervous system, including stroke, Parkinson's disease, Huntington's disease and chronic/neuropathic pain. In particular, NR2B subunit-containing NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective, with several pharmaceutical companies developing NR2B subtype-selective antagonists for several glutamate-mediated diseases. Recent studies have shown the importance of NR2B subunits for NMDA receptor localization and endocytosis, and have suggested a role for NR2B-containing NMDA receptors in the underlying pathophysiology of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. Anatomical, biochemical and pharmacological studies over the past five years have greatly added to our understanding of the role of NR2B subunit-containing NMDA receptors in chronic and neuropathic pain states, and have shown that NR2B-mediated analgesic effects might be supra- rather than intra-spinally mediated, and that phosphorylation of the NR2B subunit could be responsible for the initiation and maintenance of the central sensitization seen in neuropathic pain states. These data will hopefully provide the impetus for development of novel compounds that use multiple approaches to modulate the activity of NR2B subunit-containing NMDA receptors, thus bringing to fruition the promise of therapeutic efficacy utilizing this approach.

Topics: Animals; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Huntington Disease; Pain; Phenols; Piperidines; Protein Conformation; Receptors, N-Methyl-D-Aspartate

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.

Topics: Animals; Brain; Brain Ischemia; Conotoxins; Drug Design; Excitatory Amino Acid Antagonists; Felbamate; Glutamic Acid; Humans; Neuroprotective Agents; Phenylcarbamates; Piperidines; Propylene Glycols; Protein Conformation; Rats; Receptors, N-Methyl-D-Aspartate

Using a novel in vivo model for cerebral ischemia produced by short-lasting compression of a well-defined brain area of sensorimotor cortex we studied neuroprotective effects of the NMDA NR2B subunit selective antagonist, CP-101,606, in Sprague-Dawley rats. Cortical compression for 30 min produced a consistent and highly reproducible functional impairment, that is paresis of contralateral hind and fore limbs. The neurological deficit was accompanied by marked brain damage in cerebral cortex, hippocampus and thalamus as identified by Fluoro-Jade, a marker of general neuronal cell death. Using a daily performed beam walking test it was shown that untreated animals recovered from their functional impairment within 5-7 days following surgery. Intravenous administration of increasing doses (1, 5, 10, 20 mg/kg) of the NMDA NR2B subunit receptor specific antagonist, CP-101,606, dose-dependently improved the rate of functional recovery and protected against the ischemic brain damage in cerebral cortex, hippocampus, and thalamus as identified 2 days after the ischemic insult. Based upon these results, we conclude that NMDA NR2B receptor subunits represent potential targets to reduce not only the functional deficits, but also neuronal death in cortex and several midbrain regions produced by moderate, transient, cerebral ischemia.

Topics: Animals; Brain Ischemia; Dose-Response Relationship, Drug; Immunohistochemistry; Injections, Intravenous; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function

The neuroprotective effects of drugs that act against excitotoxic damage, caused by glutamate, are well described in focal ischemia, but behavioral effects, and apparent failure in clinical trials of "first-generation" competitive N-methyl D-aspartate (NMDA) antagonists, such as Selfotel (CGS19755), has led to interest in evaluating newer NMDA antagonists with fewer behavioral effects. We have therefore evaluated the neuroprotective effect of a new forebrain-selective polyamine site NMDA antagonist, CP101,606 in a rat subdural hematoma (SDH) model. An SDH was produced by slow injection of 0.4 ml autologous blood into the parietal subdural space. Brain damage was assessed histologically at eight coronal planes, in animals sacrificed 4 h after induction of hematoma. The drug was infused 30 min after induction of SDH. The reductions of ischemic brain damage achieved by CP101,606, was 29% for the low dose and 37% for the high dose. This novel glutamate antagonist has shown a magnitude of neuroprotection which is comparable with that seen with "first-generation" NMDA antagonists such as MK801, D-CPP-ene and CGS19755, in this same model. This new agent is claimed to have fewer psychomotor and behavioral effects than MK801, D-CPP-ene, and CGS19755.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hematoma, Subdural; Male; Neuroprotective Agents; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley

The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.. Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.. The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001).. CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Topics: Animals; Arterial Occlusive Diseases; Brain; Brain Edema; Brain Ischemia; Cats; Cerebral Arteries; Cerebral Infarction; Dialysis Solutions; Excitatory Amino Acid Antagonists; Female; Lactates; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Receptors, N-Methyl-D-Aspartate; Staining and Labeling; Tetrazolium Salts