AbstractPrevious studies have shown that magnesium salts and the noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, NPS 1506, attenuated short‐term cognitive deficits and histopathological changes associated with traumatic brain injury (TBI). We evaluated the long‐term effects of both therapies after brain trauma. Young adult rats were subjected to parasagittal fluid‐percussion brain injury and received either MgSO4 (125 μmol/400 g rat; n = 12) 15 min post‐injury, NPS 1506 (1.15 mg/kg; n = 12) 15 min and 4 hr post‐injury, or vehicle (n = 9) 15 min post‐injury. Uninjured animals (sham) received vehicle (n = 10). Learning function in these animals was evaluated using a water maze paradigm 8 months after injury or sham treatment, and the brains were examined for cortical and hippocampal tissue loss. Compared to sham animals, injured vehicle‐treated animals displayed a substantial learning dysfunction, indicated by an increased latency to find a hidden platform in the water maze (P < 0.001). No improvements in learning, however, were found for injured animals treated with NPS 1506 or MgSO4. Injury induced >30% loss of tissue in the ipsilateral cortex in vehicle‐treated animals that was not reduced in animals treated with either NPS 1506 or MgSO4. Treatment with MgSO4 significantly reduced progressive tissue loss in the hippocampus (P < 0.001). These findings are the first to demonstrate long‐term neuroprotection of hippocampal tissue by an acute treatment in a TBI model. These data also show that the previously reported broad efficacy of MgSO4 or NPS 1506 observed shortly after brain trauma could not be detected 8 months post‐injury. © 2004 Wiley‐Liss, Inc.

01 Jan 2003·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Synthesis and Brain Regional Distribution of [11C]NPS 1506 in Mice and Rat: an N-Methyl-D-aspartate (NMDA) Receptor Antagonist

Q4 · MEDICINE

Article

Author: Suhara, Tetsuya ; Haradahira, Terushi ; Maeda, Minoru ; Okauchi, Takashi ; Maeda, Jun ; Suzuki, Kazutoshi ; Arai, Takuya ; Fuchigami, Takeshi ; Yamamoto, Fumihiko ; Sasaki, Shigeki

NPS 1506 [3-fluoro-gamma-(3-fluorophenyl)-N-methylbenzenepropamine] is representative of a non-psychotomimetic class of N-methyl-D-aspartate (NMDA) receptor antagonists. [11C]NPS 1506 was prepared at high radiochemical purity (>98%) with a specific activity of around 50 GBq/micromol at the end of synthesis by methylation of the desmethyl precursor with [11C]methyl iodide in the presence of NaH. Biodistribution of [11C]NPS 1506 in mice and rat demonstrated that uptake into the brain was rapid and occurred at high levels. [11C]NPS 1506 showed no appreciable specific binding in rodent brains under in vivo conditions, possibly because of both a large non-specific bound fraction and low in vitro binding affinity for NMDA receptors.

01 Dec 2000·Experimental NeurologyQ2 · MEDICINE

NPS 1506 Attenuates Cognitive Dysfunction and Hippocampal Neuron Death Following Brain Trauma in the Rat

Q2 · MEDICINE

Article

Author: Xiao-Han Chen ; Matthew J. Leoni ; Tracy K. McIntosh ; Douglas H. Smith ; Jessica Cheney ; Alan L. Mueller

Although several noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to be substantially efficacious in experimental models of brain trauma, side effects associated with this class of compounds have impeded clinical application. Therefore, new noncompetitive NMDA receptor antagonists have been developed, including NPS 1506, that appear to be nontoxic but retain efficacy. In the present study, we evaluated the efficacy of NPS 1506 in a model of parasagittal fluid percussion brain trauma in the anesthetized rat. Administration of 1 mg/kg NPS 1506 at both 10 min and 4 h posttrauma induced no changes in brain temperature, mean arterial pressure, pulse, or arterial blood gasses. At 1 week postinjury, animals treated with the same dosing regimen of NPS 1506 demonstrated a dramatic attenuation of memory dysfunction evaluated by a water maze task (P < 0.02) and had greatly reduced neuron death in the CA3 subfield of the hippocampus (P < 0.01). However, NPS 1506 treatment did not significantly affect the extent of cortical tissue loss following injury. Since memory dysfunction and hippocampal damage are common and potentially related consequences of brain trauma in humans, our results suggest that NPS 1506 treatment may have clinical utility.

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Indication	Highest Phase	Country/Location	Organization	Date
Craniocerebral Trauma	Phase 1	US	NPS Pharmaceuticals, Inc.	-
Depressive Disorder, Major	Phase 1	-	Shire Pharmaceuticals Services Ltd.	-
Depressive Disorder, Major	Phase 1	US	NPS Pharmaceuticals, Inc.	-
Stroke	Phase 1	US	NPS Pharmaceuticals, Inc.	-

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