NMDA receptors toxicity

University of Rochester, Behavioral toxicity of lead role of the Rochester, NY NMDA receptor... 

Shimosato K., Marley R., Saito T. Differential effects of NMDA receptor and dopamine receptor antagonists on cocaine toxicities. Pharmacol. Biochem. Behav. 51, 1995. 

The second phase of the process involves a massive increase in intracellular calcium concentrations. Interestingly, the calcium entry through NMDA receptors is particularly toxic, with one immediate pathogenic target of calcium entry being the mitochondrion [19]. 

Reactive oxygen species may modify both the excito-toxic and the apoptotic components of ischemic brain damage. In addition to direct effects of oxidative injury during ischemia-reperfusion, ROS may modify ischemic excitotoxicity by downregulating current through NMDA receptors. However, exposure to oxidative stress can be... 

Interest in the therapeutic potential of drugs acting on the NMDA receptor has risen with the discovery that epilepsy and related convulsive states may occur as a consequence of a sudden release of glutamate. Sustained seizures of the limbic system in animals result in brain damage that resembles the changes seen in glutamate toxicity. Similar changes are... 

Cell culture studies have shown that carnosine is protective against the toxicity of the Ap-peptide which accumulates in the AD brain. The dipeptide prevented Ap-peptide (l-42)-induced glutamate release, but increased expression of the NMDA receptor. It was proposed that camosine s protective activity was exerted via regulation of glutamate release and independent of the carnosine-histidine-histamine axis (Fu et al,... 

Persistent excitatory glutamatergic stimulation of postsynaptic NMDA receptors, which may cause neuronal toxicity by allowing excessive calcium entry into neurons, has been implicated in the symptomatology of dementia of the Alzheimer s type (Farber et al. 1998). Memantine is a moderate-affinity, noncompetitive inhibitor of NMDA receptors (Danysz et al. 2000). 

The toxic action of NO has an important role, especially in nerve systems. It is assumed that during a stroke, for example, excess production of NO leads to death of nerve cells. Direct modification of ligand-gated ion chaimels, such as the receptor for N-methyl-D-aspartate (NMDA receptor), by NO has a special role in coimection with this. 

Acamprosate Poorly understood NMDA receptor Reduced risk of relapse in individuals with alcoholism Toxicity Gastrointestinal effects and rash... 

The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors and fuel additives enhance GABAa receptor function. Most inhalants produce euphoria increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite ("poppers"), primarily produce smooth muscle relaxation and enhance erection, but are not addictive. With chronic exposure to the aromatic hydrocarbons (eg, benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive. 

Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade. This drug appears to be better tolerated and less toxic than the cholinesterase inhibitors. Memantine is available as Namenda in 5 and 10 mg oral tablets. 

Black, M., Lanthorn, T., Small, D., Mealing, G., Lam, V., Morley, P. Study of potency, kinetics of block and toxicity of NMDA receptor antagonists using fura-2, Eur. J. Pharmacol. 1996, 317, 377-381. 

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