3-Nitropropionic acid toxicity in hippocampus: Protection throughN-methyl-D-aspartate receptor antagonism

Abstract

The over-activation of glutamate receptors can lead to excitotoxic cell death and is believed to be involved in the progression of neurodegenerative events in the vulnerable hippocampus. Here, we used an in vitro slice model to study toxicity produced in the hippocampus by the mitochondrial toxin 3-nitropropionic acid (3-NP). The organotypic slice cultures exhibit native cellular organization as well as dense arborization of neuronal processes and synaptic contacts. The hippocampal slices were exposed to 3-NP for 2-20 days, causing calpain-mediated breakdown of the spectrin cytoskeleton, a loss of pre- and postsynaptic markers, and neuronal atrophy. The N-methyl-D-aspartate (NMDA) receptor antagonist memantine reduced both the cytoskeletal damage and synaptic decline in a dose-dependent manner. 3-NP-induced cytotoxicity, as determined by the release of lactate dehydrogenase, was also reduced by memantine with EC50 values from 1.7 to 2.3 microM. Propidium iodide fluorescence and phase contrast microscopy confirmed memantine neuroprotection against the chronic toxin exposure. In addition, the protected tissue exhibited normal neuronal morphology in the major hippocampal subfields. These results indicate that antagonists of NMDA-type glutamate receptors are protective during the toxic outcome associated with mitochondrial dysfunction. They also provide further evidence of memantine's therapeutic potential against neurodegenerative diseases.

Protective effects of epigallocatechin gallate following 3-nitropropionic acid-induced brain damage: possible nitric oxide mechanisms

“…It has also been reported that systemic 3-NP administration produces oxidized proteins in the striatum and cortex as well as massive loss Fontaine 2000). Researchers also confirmed 3-NP-induced lesions and oxidative damage in hippocampus (Rodríguez-Martínez et al 2004;Silva et al 2007;Karanian et al 2006;Burda et al 2005). Turan and coworkers reported that chemical preconditioning with 3-NP reduces infarct size via a mechanism that may involve increased bioavailability of NO and decreased ONOOformation (Turan et al 2006).…”

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

“…Moreover, memantine was neuroprotective against rotenone, which an inhibitor of mitochondrial complex I (Rojas et al 2008) and reduced ROS and lipid peroxidation induced by organophosphate in rat brain (Zaja-Milatovic et al 2009). Memantine also prevent the deleterious effects of mitochondrial dysfunction induced by complex II inhibitors, malonate and 3-nitropropionic acid (Schulz et al 1996;Karanian et al 2006;Volbracht et al 2006). In brain tissue, it was showed that the complex I site can contribute up to 50% of total ROS generation (Kudin et al 2008).…”

Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone

“…Schulz et al (1996), reported that memantine prevented the volumetric changes in the mouse striatum following administration of malonate, a complex II inhibitor, demonstrating that memantine could be used to prevent the deleterious effects of mitochondrial dysfunction. In vitro studies have shown that memantine diminishes the toxicity induced by 3-nitropropionic acid, another complex II inhibitor, in cerebellar granular cell cultures (Volbracht et al, 2006), cholinergic neurons (Wenk et al, 1996), and hippocampal slices (Karanian et al, 2006). Despite the evidence supporting a relevant role of complex I inhibition in neurodegeneration, the effects of memantine against complex I inhibition have remained largely unexplored.…”