Prevention of Apoptotic Neuronal Death by GM1 Ganglioside

Ferrari, Giovanna; Anderson, Blake; Stephens, Robert M.; Kaplan, David R.; Greene, Lloyd A.

doi:10.1074/jbc.270.7.3074

Cited by 201 publications

(145 citation statements)

References 68 publications

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“…In cultured cerebellar granule cells, a natural ganglioside, GM1 (6), as well as other synthetic gangliosides, block glutamate-mediated cell death without affecting the function of NMDA or other glutamate-operated cation channels (37). Interestingly, GM1, which does not affect synthesis of neurotrophins, has been shown to mimic neurotrophin activity by increasing Trk function (28,38,39). When compared with BDNF, both GM1 and NMDA elicit a modest increase in Trk tyrosine phosphorylation; however, both compounds prevent glutamate excitotoxicity, suggesting that there could be cross-talk between two or more signaling pathways resulting in a synergism or potentiation of the effect, perhaps via different substrates.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Marini¹,

Rabin²,

Lipsky³

et al. 1998

Journal of Biological Chemistry

193

221

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The molecular mechanism(s) of N-methyl-D-aspartate (NMDA) neuroprotective properties were investigated in primary cultures of cerebellar granule cell neurons. Granule cells express the neurotrophin receptor TrkB but not TrkA or TrkC. In these cells, the TrkB ligand brain-derived neurotrophic factor (BDNF) prevents glutamate toxicity. Therefore, we have tested the hypothesis that NMDA activates synthesis and release of BDNF, which may prevent glutamate toxicity by an autocrine loop. Exposure of granule cells for 2 and 5 min to a subtoxic concentration of NMDA (100 M) evoked an accumulation of BDNF in the medium without concomitant changes in the intracellular levels of BDNF protein or mRNA. The increase in BDNF in the medium is followed by enhanced TrkB tyrosine phosphorylation, suggesting that NMDA increases the release of BDNF and therefore the activity of TrkB receptors. To examine whether BDNF and TrkB signaling play a role in the NMDA-mediated neuroprotective properties, neurons were exposed to soluble trkB receptor-IgG fusion protein, which is known to inhibit the activity of extracellular BDNF, and to K252a, a tyrosine kinase inhibitor. Both compounds blocked the NMDA-mediated TrkB tyrosine phosphorylation and subsequently its neuroprotective properties. We suggest that NMDA activates the TrkB receptor via a BDNF autocrine loop, resulting in neuronal survival.Glutamate, the endogenous neurotransmitter required for normal physiological excitation, is also involved in the pathophysiology of hypoxic/ischemic neuronal injury (1-3). Although this neuropathological process can be mediated by any of the excitatory amino acid receptors, the N-methyl-D-aspartate (NMDA) 1 glutamate receptor subtype plays a major role. In addition, NMDA receptors mediate adaptive responses important for synaptic plasticity during development (4, 5). The molecular mechanism(s) by which NMDA receptors mediate such opposing effects are not clear.The role of NMDA receptors in glutamate-mediated excitotoxicity has been studied in rat cerebellar granule cells in vitro, in which overactivation of NMDA receptors results in neuronal cell death (6 -8). Paradoxically, in these cells subtoxic concentrations of NMDA have been shown to protect vulnerable neurons against an excitotoxic concentration of glutamate (9). Moreover, recent studies have shown that the neuroprotective effect of NMDA is blocked by coincubation with either the RNA synthesis inhibitor actinomycin D or the protein synthesis inhibitor cycloheximide (9). Thus, the neuroprotective effect of NMDA may involve a polypeptide(s) with neuroprotective properties.Cerebellar granule cells are responsive to various neurotrophic factors and in particular to the neurotrophins (10, 11), a family of trophic factors related by primary amino acid sequence homology, whose members include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and NT-4/5 (12-17). The biological activity of neurotrophins depends upon the activation of high-affinity receptors (Trk...

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Section: Discussionmentioning

confidence: 99%

Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Marini¹,

Rabin²,

Lipsky³

et al. 1998

Journal of Biological Chemistry

193

221

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“…They have been implicated in several biological processes including cell-cell recognition, regulation of cell growth and differentiation and signal transduction [20]. The ganglioside GM-1 has previously been shown to act as a survival factor in both neuronal cells and cardiac fibroblasts [21,22]. Maulik et al [23] initially showed that GM-1 can reduce I/R injury in an isolated rat heart by Langendorff technique and had suggested that the likely mechanisms included inhibition of calcium overloading and scavenging of free radicals generated during the reperfusion of myocardium.…”

Section: Sphingolipids and Myocardial I/r Injurymentioning

confidence: 99%

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Gundewar

Lefer

2008

Biochimica et Biophysica Acta (BBA) - General Subjects

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Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggests that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia reperfusion injury and their possible mechanisms of cardioprotection.

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“…Thus, apoptosis can be mimicked by the addition of exogenous, soluble C 2 -or C 6 -ceramides or bacterial sphingomyelinase and sphingosine derivatives, but cannot be induced by other lipids (apart from sphingosine whose role in apoptosis is also under investigation) or by other lipases (such as phospholipase C). In fact, both diacylglycerol (35) and gangliosides, specifically, G M1 (36,37), have been reported to have a protective effect indicating that the exogenous ceramide did not induce apoptosis by a nonspecific membrane effect. However, whether ceramide is necessary for any and/or all types of apoptosis and the time course of its action remains to be fully elucidated.…”

mentioning

confidence: 99%

Anti-immunoglobulin-induced Apoptosis in WEHI 231 Cells Involves the Slow Formation of Ceramide from Sphingomyelin and Is Blocked by bcl-xL

Wiesner

Kilkus²,

Gottschalk

et al. 1997

Journal of Biological Chemistry

116

119

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Prolonged (>24 h) exposure to anti-IgM (an antigen surrogate that induces membrane cross-linking and apoptosis) induced a 3-fold increase in the mass of endogenous ceramide measured by 32 P labeling by diacylglycerol kinase and a 4-fold increase in ceramide as measured by metabolic labeling with [ 3 H]palmitate in a B-lymphocyte cell line, WEHI 231. This correlated with the induction of apoptosis. Shorter exposure times to anti-IgM (up to 8 h) failed to elicit apoptosis and did not elicit increased ceramide formation. After 8 h, apoptosis occurs concomitantly with ceramide formation over the next 40 h. Further, we showed that exogenous ceramide mimicked anti-IgM-induced apoptosis and that apoptosis was potentiated in serum-free media. Treatment of cells with an inhibitor of ceramide catabolism, Noleoylethanolamine, increased both ceramide formation and apoptosis and accelerated apoptosis induced by anti-IgM. To examine further how ceramide metabolism is involved in apoptosis, we derived cell lines from a small population of cells resistant to N-oleoylethanolamine. These cell lines were selected based on an altered ceramide metabolic pathway, were resistant to apoptosis induced by anti-IgM, and showed no significant increase in ceramide when challenged with anti-IgM. The basis of this resistance was shown to be the failure to activate neutral sphingomyelinase activity following 24-h treatment with anti-IgM, in contrast to the 2-fold increase in neutral sphingomyelinase activity observed in wild type cells. We have shown previously that transfection of WEHI cells with bcl-x L conferred resistance to anti-IgMinduced apoptosis, whereas transfection with bcl-2 did not (Gottschalk, A., Boise, L., Thompson, C., and Quintans, J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 7350 -7354). In this study, these bcl-x L transfectants also displayed increased resistance to exogenous N-acetylsphingosine (C 2 -ceramide) or N-hexanoylsphingosine (C 6 -ceramide). However, when challenged with anti-IgM the bcl-x L transfectants produced levels of ceramide similar to wild type cells, suggesting that ceramide formation is upstream of bcl-x L and that it is a major determinant of B-cell death.Apoptosis (1) can be induced readily in lymphocytes by means of irradiation, corticosteroids, or cross-linking of their antigen receptors. The apoptotic response of the murine Blymphoma WEHI 231 cell line to the cross-linking of surface IgM receptors provides a model to study the induction of physiological cell death (apoptosis) in lymphocytes (2-4). In WEHI 231, the response is specifically triggered via surface IgM since cross-linking other surface proteins such as IgD, Fc receptor, or major histocompatibility complex class II have no effect (5). Apoptosis is reversed by both phorbol esters and by bacterial lipopolysaccharide (6). Apoptosis can also be reversed by the removal of the antigen prior to 12 h of exposure, emphasizing its slow acting nature compared with necrosis and some types of apoptosis. We showed recently that the time course and ...

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Prevention of Apoptotic Neuronal Death by GM1 Ganglioside

Cited by 201 publications

References 68 publications

Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Anti-immunoglobulin-induced Apoptosis in WEHI 231 Cells Involves the Slow Formation of Ceramide from Sphingomyelin and Is Blocked by bcl-xL

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