**Background**
Ischemic brain injury, such as that caused by stroke, often leads to extensive neuronal death and permanent neurological deficits. A primary driver of this damage is the overactivation of N-methyl-D-aspartate (NMDA) receptors, which triggers an excessive influx of calcium ions and the subsequent production of reactive oxygen species (ROS). This cascade of excitotoxicity and oxidative stress results in the degeneration of both neurons and glia. Therefore, developing agents that can selectively inhibit NMDA receptors while simultaneously scavenging free radicals is a critical strategy for neuroprotection. In this context, we will introduce a potent NR2B-selective antagonist and free radical scavenger – Nelonemdaz.
**Definition**
Nelonemdaz (Salfaprodil free base) is an NR2B-selective and uncompetitive antagonist of the NMDA receptor that also functions as a free radical scavenger.
**In Vitro and In Vivo Studies**
According to the Nelonemdaz description, this compound exhibits dual-action neuroprotection against both NMDA-induced and free radical-induced cell death. In terms of Nelonemdaz in vitro activity, concentrations of 10-300 μM provide apparent neuroprotection against 300 μM NMDA, with significant effects observed at doses as low as 30 μM. Furthermore, Nelonemdaz (10-500 μM) inhibits the electrophysiologic response of cultured cortical neurons to 300 μM NMDA in a concentration-dependent manner. Its antioxidant properties are equally potent; Nelonemdaz (0.1-1 μM) markedly reduces Fe2+-induced neurotoxicity and blocks the degeneration of neurons and glia in cortical cultures. Specifically, it effectively scavenges superoxide radicals (IC50 = 63.07±1.44 μM), nitric oxide (IC50 = 155.8±4.88 μM), and hydroxyl radicals (IC50 = 58.45±1.74 μM). Additionally, it inhibits malondialdehyde (MDA) formation with an IC50 of 2.72±0.26 μM and reduces iron-ascorbate-induced lipid peroxidation (IC50 = 24.56±0.07 μM).
Regarding Nelonemdaz in vivo efficacy, studies using male Sprague-Dawley rats in middle cerebral artery occlusion (MCAO) models demonstrated significant benefits. Administration of Nelonemdaz (0.5-20 mg/kg; i.v.) 5 minutes after reperfusion reduced cerebral infarct volume dose-dependently, with a maximal reduction of 66% at doses of 2.5 to 5 mg/kg. At a dose of 5 mg/kg, no neuronal damage was observed in the most vulnerable cortical areas. In intraluminal thread occlusion models, i.v. administration of 5 mg/kg 30 minutes after reperfusion substantially reduced infarct volume in the cortex and striatum, as well as white matter damage in the striatum and external capsule, without altering physiologic variables such as arterial pH or PCO2. In conclusion, Nelonemdaz is a potent NR2B-selective NMDA antagonist and antioxidant that provides comprehensive neuroprotection against ischemic brain injury.
Keywords
Nelonemdaz, 640290-67-1, Salfaprodil, Neu2000, Neu 2000, Neu-2000, iGluR, Ionotropic glutamate receptors, NMDA, neuroprotection, antioxidant, free, radical, scavenger
References
[1] Gwag BJ, et al. Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine. J Cereb Blood Flow Metab. 2007 Jun;27(6):1142-51.
[2] Sung IC, et, al. Neu2000, an NR2B-selective, Moderate NMDA Receptor Antagonist and Potent Spin Trapping Molecule for Stroke. Drug News Perspect. 2010 Nov; 23(9): 549-56.
[3] Nishant PV, et, al. Antioxidant Properties of Neu2000 on Mitochondrial Free Radicals and Oxidative Damage. Toxicol In Vitro. 2013 Mar; 27(2): 788-97.