Excitotoxic and excitoprotective mechanisms

Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
NeuroMolecular Medicine (Impact Factor: 3.68). 02/2003; 3(2):65-94. DOI: 10.1385/NMM:3:2:65
Source: PubMed

ABSTRACT Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.

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    • "The programed cell death (apoptosis) is a biological process in which unwanted and/or damaged cells are killed, so that the organism could maintain homeostasis. The apoptosis process is a characteristic not only of normal development but also of numerous neurodegenerative diseases and neurological conditions, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease, and stroke (Bamberger and Landreth 2002; Jenner 2003; Mattson 2003; McLaughlin et al. 1998; Morishima et al. 2001). Keep in mind that in the neurodegenerative diseases, neuronal cells death occurs not only via apoptosis but also in the necrosis. "
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    ABSTRACT: 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) was shown to be neurotoxic to the dopaminergic neurons, and thus it was proposed to be an endogenous risk factor leading to Parkinson's disease. In order to better understand the molecular mechanisms of 1BnTIQ-produced toxicity, we examined the impact of different concentrations of 1BnTIQ (50, 100, and 500 μM) on glutamate-induced apoptotic pathway. We measured the markers of apoptosis, such as caspase-3 activity, lactate dehydrogenase release, and mitochondrial membrane potential. Molecular data were supported at the cellular level by calcein AM and Hoechst 33342 staining. The obtained data demonstrated concentration-dependent effects of 1BnTIQ opposing apoptosis, and evidenced that 1BnTIQ in a low concentration (50 μM) exhibited neuroprotective activity, whereas in 10 times higher concentration (500 μM) might be neurotoxic, and significantly intensified glutamate-induced increase in apoptosis markers. Additionally, using an ex vivo molecular study we indicated that both acute and chronic administration of 1BnTIQ did not affect the level of alpha synuclein and tyrosine hydroxylase protein in the rat substantia nigra. Summarizing the studies, we suggest that 1BnTIQ is a rather weak endogenous neurotoxin; however, it should be taken into account that in higher μmoles concentrations, it can initiate apoptosis in the central nervous system and may be involved in the etiopathology of neurodegenerative diseases.
    Neurotoxicity Research 11/2013; 25(1). DOI:10.1007/s12640-013-9436-x · 3.54 Impact Factor
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    • "A breakthrough in ALS research was the discovery that non cell-autonomous processes due to functional dysregulation of surrounding non-neuronal cells, i.e. microglia and astrocytes, contribute to motor neuron death [1], [18]. Several studies showed that astrocytes are specific contributors to spinal motor neuron degeneration in mutant SOD1-linked ALS and that they exert toxicity on motor neurons via release of soluble factors [2], [19]. We therefore further analysed the protective effects of MSC CM pre-treatment in primary astrocyte cultures derived from either SOD1G93A or non-transgenic mice to determine whether astrocytes from mutant animals respond differently to MSC CM. "
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    ABSTRACT: Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.
    PLoS ONE 09/2013; 8(9):e72926. DOI:10.1371/journal.pone.0072926 · 3.23 Impact Factor
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    • "Glu concentration at the synaptic cleft requires tight regulation in order to avoid excitotoxic neuronal death (Mattson, 2003; Olney, 2003). Such regulation is accomplished through the removal of Glu by a family of Na+-dependent transporters expressed in neurons and glia (Danbolt, 2001). "
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    ABSTRACT: Glutamate, the excitatory transmitter at the main signaling pathway in the retina, is critically involved in changes in the protein repertoire through the activation of signaling cascades, which regulate protein synthesis at transcriptional and translational levels. Activity-dependent differential gene expression by glutamate is related to the activation of ionotropic and metabotropic glutamate receptors; however, recent findings suggest the involvement of Na+-dependent glutamate transporters in this process. Within the retina, glutamate uptake is aimed at the replenishment of the releasable pool, and to the prevention of excitotoxicity, and is carried mainly by the Na+-dependent glutamate/aspartate transporter (GLAST/EAAT-1) located in Müller radial glia. Based on previous work showing the alteration of GLAST expression induced by glutamate, the present work investigates the involvement of GLAST signaling in the regulation of protein synthesis in Müller cells. To this end, we explored the effect of D-Aspartate on serine 2448 mTOR (mechanistic target of rapamycin) phosphorylation in primary cultures of chick Müller glia. Results showed that D-Aspartate transport induces the time- and dose-dependent phosphorylation of mTOR, mimicked by the transportable GLAST inhibitor THA (threo-b-hydroxyaspartate). Signaling leading to mTOR phosphorylation includes Ca2+ influx, the activation of p60src, phosphatidylinositol 3-kinase, protein kinase B, mTOR and p70S6K. Interestingly, GLAST activity promoted AP1 binding to DNA supporting a function for transporter signaling in retinal long-term responses. These results add a novel receptor-independent pathway for glutamate signaling in Müller glia, and further strengthen the critical involvement of these cells in the regulation of glutamatergic transmission in the retina.
    ASN Neuro 07/2012; 4(5). DOI:10.1042/AN20120022 · 4.02 Impact Factor
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