NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience

Mueller, Alan L.; Artman, Linda D.; Balandrin, Manuel F.; Brady, Edward J.; Chien, Yongwei; DelMar, Eric G.; Kierstead, A.; Marriott, Thomas B.; Moe, Scott T.; Raszkiewicz, Joanna L.; VanWagenen, B.; Wells, David S.

doi:10.1007/s007260070047

Cited by 6 publications

(2 citation statements)

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“…The dosing regimens for NPS 1506 and MgSO 4 were based on previously published studies showing neuroprotection shortly after brain injury in the rat (Smith et al, 1993; Muir et al, 1999; Leoni et al, 2000; Mueller et al, 2000). After injury, animals were assigned randomly to receive vehicle, NPS 1506, or MgSO 4 .…”

Section: Methodsmentioning

confidence: 99%

Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Browne

Leoni

Iwata

et al. 2004

J of Neuroscience Research

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Previous 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 MgSO(4) (125 micromol/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 MgSO(4). 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 MgSO(4). Treatment with MgSO(4) 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 MgSO(4) or NPS 1506 observed shortly after brain trauma could not be detected 8 months post-injury.

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Section: Methodsmentioning

confidence: 99%

Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Browne

Leoni

Iwata

et al. 2004

J of Neuroscience Research

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“…Psychomimetic, cardiovascular, and neurotoxic effects appear to limit the therapeutic potential of potent NMDA antagonists (Olney et al , 1991; Muir and Lees, 1995; Krystal et al , 2003). Moderate affinity, uncompetitive NMDA antagonists such as memantine, and NPS 1506 do not show undesirable side effects within the therapeutic range for neuroprotection (Parsons et al , 1999; Mueller et al , 2000; Labiche and Grotta, 2004). We have shown that Neu2000 is an uncompetitive NMDA antagonist that spares neurologic behaviors after ischemic injury and does not cause neurotoxicity, suggesting that it is a secure NMDA antagonist suitable for treating stroke.…”

Section: Discussionmentioning

confidence: 99%

Marked Prevention of Ischemic Brain Injury by Neu2000, an NMDA Antagonist and Antioxidant Derived from Aspirin and Sulfasalazine

Gwag

Lee

et al. 2006

J Cereb Blood Flow Metab

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Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxicischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 lmol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

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Clinical Trials with Drugs Targeting Ionic Channels, Antiporters, and Pumps in Ischemic Stroke

Spinali

Pignataro

Renzo

et al. 2009

New Strategies in Stroke Intervention

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NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience

Cited by 6 publications

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Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Marked Prevention of Ischemic Brain Injury by Neu2000, an NMDA Antagonist and Antioxidant Derived from Aspirin and Sulfasalazine

Clinical Trials with Drugs Targeting Ionic Channels, Antiporters, and Pumps in Ischemic Stroke

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NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience

Cited by 6 publications

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Acute treatment with MgSO4 attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Acute treatment with MgSO4 attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Marked Prevention of Ischemic Brain Injury by Neu2000, an NMDA Antagonist and Antioxidant Derived from Aspirin and Sulfasalazine

Clinical Trials with Drugs Targeting Ionic Channels, Antiporters, and Pumps in Ischemic Stroke

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Product

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Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat

Acute treatment with MgSO₄ attenuates long‐term hippocampal tissue loss after brain trauma in the rat