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Protection of taurine and granulocyte colony-stimulating factor against excitotoxicity induced by glutamate in primary cortical neurons
© Prentice and Wu; licensee BioMed Central Ltd. 2010
Published: 24 August 2010
Both taurine, an inhibitory neurotransmitter and granulocyte colony-stimulating factor (G-CSF), a growth factor, possess neuroprotective and neurotrophic properties in vitro. However, the mechanisms of their underlying neuroprotective effects are not fully understood.
In the present study, we investigated the potential protective benefits of taurine, G-CSF and the combination of taurine and G-CSF against excitotoxicity induced by glutamate in primary cortical neuronal cultures.
25 mM taurine, 25 ng/ml G-CSF and the combination of 25 mM taurine and 25 ng/ml G-CSF showed a protective effect reaching 75%, 75% and 88%, respectively. Furthermore, taurine exerted its protective effect through down-regulation of expression of GRP 78, CHOP, Bim and caspase 12.
The results showed that all of these treatments, taurine, G-CSF and the combination of taurine and G-CSF, protected primary cortical neurons against excitotoxicity induced by glutamate. ER stress is suppressed by taurine after glutamate toxicity.
Taurine (2-aminoethanesulfonic acid), an inhibitory neurotransmitter, is present at high concentrations in many invertebrate and vertebrate systems [1–3]. Taurine has received much attention in the field of neuroprotection since the original experiments of Curtis and Watkins on the synaptic effects of inhibitory and excitatory amino acids [4, 5]. Taurine is at a high level in the immature brain, serving as a trophic factor . It has been thought to induce hyperpolarization, to inhibit firing of central neurons and to act as a modulator of synaptic activity in the brain [7–9]. The maintenance of the integrity of membranes, transmembrane Cl- flux and intracellular calcium homeostasis are also important functions of taurine in the brain [10–13]. Taurine also acts as an osmoregulator and plays an antioxidant role [14–16]. In addition, it has been related to neuroprotection against multiple neurological diseases including Alzheimer’sdisease, Huntington’s disease and brain ischemia [17–19]. Moreover, taurine was found in neuronal systems to exert a protective function against toxicity induced by glutamate [20, 21].
G-CSF is one of the few growth factors currently approved for clinical use for routine treatment of neutropenia . It primarily stimulates proliferation, differentiation and maturation of cells committed to the neutrophilic granulocyte lineage through binding to the specific G-CSF receptor . G-CSF also has been shown to have trophic effects on neuronal cells in vitro . Moreover, G-CSF is an effective neuroprotectant in the treatment of a number of neurological diseases including stroke, Parkinson’s disease and Alzheimer’s disease [25–28]. In addition, apart from its protective role in neurons, G-CSF also dampens systemic inflammatory reactions, which may be of additional benefit in neurodegenerative conditions .
Although it is established that taurine and G-CSF have many beneficial effects under a variety of conditions of cell damage, the protective mechanisms are still unclear. We have recently demonstrated that taurine protects PC12 cells against ER stress induced by oxidative stress . Here, we studied the protective effect of taurine, G-CSF and the combination of taurine and G-CSF against excitotoxicity induced by glutamate in rat primary neuronal cultures. We demonstrated that ER stress is also involved in the excitotoxicity induced by glutamate. Moreover, taurine protects primary neurons by suppressing ER stress induced by glutamate.
Basal medium-Eagle, fetal bovine serum, poly-D-lysine, taurine, Penicillin-Streptomycin and other chemicals were purchased from Sigma (St. Louis, MO, USA). Mouse anti-actin, rabbit anti-GRP78, rabbit anti-CHOP/GADD153, rabbit anti-caspase-12 antibodies and secondary mouse and rabbit antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Rabbit anti-Bim antibody was purchased from Assay Designs (Ann Arbor, Michigan, USA). Adenosine 5’-triphosphate (ATP) Bioluminescent assay kit was purchased from Promega (Madison, WI, USA). RIPA buffer was purchased from Thermo Scientific (Rockford, IL, USA). Pregnant Sprague Dawley rats were purchased from Harlan (Indianapolis, IN) and housed in the animal care facility at Florida Atlantic University. The procedures for the care and use of rats, in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, were approved by the Institutional Animal Care and Use Committee of Florida Atlantic University.
Primary cortical neuronal cell culture
Primary cortical neuronal cell cultures were prepared using a previously described protocol . Briefly, rat embryos at 17-18 days were removed and brains were isolated from the fetuses and kept in basal media Eagle (BME) supplemented with 2 mM glutamine, 26.8 mM glucose, and 20% heat-inactivated fetal bovine serum. This medium is referred to as growth medium-eagle (GME). The cortices then were dissociated by passing the tissue through a 14-G cannula. Cells were centrifuged at 200 g/min for 5 min at 25oC. The resulting pellet was resuspended in GME and plated on appropriate tissue culture plates precoated with 5 ug/ml of poly-D-lysine. Cells were maintained for 1 hour in a humidified incubator (37oC, 99% humidity and 5% CO2) before the incubation medium was replaced with serum-free neurobasalmedium (GIBCO) supplemented with B27 and 500 uM glutamine. The cultures were maintained in an incubator for 14 -18 days.
Measurement of cell viability
Cells were measured by ATP assay. Neurons at 14 days in vitro were preincubated with 25 mM taurine for 1 hour. Then the neurons were treated with 100 uM glutamate for 4 hours. ATP solution was added to each well and cells were incubated for 10 minutes, after which levels of ATP were quantified in a luciferase reaction. The luminescent intensity was measured using a luminometer (SpectraMax, Molecular Devices) after transferring the lysate to a standard opaque walled multi-well plate.
Western blot analysis
Primary cortical neuron cultures were lysed in RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) containing 1% (v/v) mammalian protease inhibitor cocktail from Sigma and separated on a SDS-PAGE. After proteins were transferred to a nitrocellulose membrane, the membrane was then blocked in blocking buffer (20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween-20, 5% milk) for 1.5 hours at room temperature. After blocking, the corresponding primary antibody was incubated for one hour, followed by one hour incubation with the corresponding HRP-conjugated secondary antibody at room temperature. Extensive washes with blocking buffer were performed between each step. The protein immuno-complex was visualized using ECL detection reagents.
All data shown were expressed as the mean ± SEM. The Student’s t-test or one-way ANOVA was used to compare means between groups. Differences of P<0.05 were considered statistically significant.
Dose-dependent glutamate toxicity in primary neuron cultures
Protective effects of taurine against glutamate toxicity in primary neuron cultures
Protection of G-CSF against glutamate toxicity in primary neuronal cultures
The protective effect of the combination of taurine and G-CSF in primary neuronal cultures
Taurine protects neurons against glutamate excitotoxicity by suppressing the expression of GRP78, CHOP, Caspase-12 and Bim
In the present study, we have demonstrated the potent protection by taurine and by G-CSF in an in vitro model of primary cortical neuronal cell death induced by glutamate. Taurine and G-CSF protected primary cortical neurons against glutamate-induced neurotoxicity as determined by measuring cell viability using the ATP assay. On the other hand, we found that the combination of taurine and G-CSF gave a synergistic enhancement of protection against glutamate in primary cortical neurons. We have further shown that the suppression of ER stress is an essential underlying mechanism for taurine-induced neuroprotection. Our investigation of the intracellular mechanisms downstream of ER stress demonstrated a reversal by taurine of glutamate-induced increases in GRP78, CHOP, Caspase-12 and Bim levels.
A previous paper reported that taurine and basic fibroblast growth factor (bFGF) in combination gave an enhanced neuroprotection in granule neurons against glutamate induced excitotoxicity . They showed that neuroprotection was obtained only through the combined action of taurine and bFGF in a cerebellar granule neuron rich culture, but not by these factors alone. Therefore, they believed that taurine can augment bFGF function under certain conditions. Here, we demonstrated that taurine or G-CSF administrated alone showed a neuroprotective effect. Furthermore, an enhanced protection against glutamate was also observed with a combination of taurine and G-CSF. The clinical application of taurine was investigated and found to be effective in studies as early as 1974 when it was applied to treatment for refractory epilepsy . Both taurine and G-CSF have been shown to be potential drugs for ischemia or stroke in clinical applications [44, 45]. Since the combination of taurine and G-CSF have synergistic neuroprotective effects against glutamate excitotoxicity, as demonstrated in this paper, this strongly suggests that the combination of taurine and G-CSF may be more effective than the individual agents in treatment of neurological diseases, such as stroke.
Many neurological disorders such as Alzheimer’s disease, stroke and Parkinson’s disease have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury [46–48]. Previous studies have also shown that ER stress is induced in neurons by glutamate toxicity [49, 50]. Recently, kainic acid (KA), a non-NMDA glutamate receptor agonist, was found to cause the disintegration of the ER membrane in hippocampal neurons and to cause ER stress . In this study, we demonstrated glutamate induced ER stress associated with the up-regulation of the proteins GRP78, CHOP, Bim and caspase-12.
Although taurine has been investigated and applied to treat many diseases, the protective mechanism is still not fully understood. We have already demonstrated that ER stress induced by H2O2 in PC12 cells was prevented by taurine treatment . In the present study, our results show that taurine reduces the ER stress induced by glutamate in primary neuronal cultures.
In the present study, we demonstrated that both taurine and G-CSF protect primary cortical neurons against glutamate-induced cell death. Interestingly, we found that the combination of taurine and G-CSF results in an enhanced protective effect. Because both taurine and G-CSF are neuroprotective agents that are approved for clinical use, the combined administration of these two factors may constitute a viable therapy with potentially enhanced therapeutic efficacy. Moreover, taurine suppressed the ER stress induced by glutamate. Further investigation will be performed to examine the specific pathway responsible for ER stress induced by glutamate and to identify molecular targets in the ER stress pathway that are specifically inhibited by taurine, G-CSF and their combination.
This work was supported in part by the James and Esther King Biomedical Research Program, Florida Department of Health.
This article has been published as part as part of Journal of Biomedical Science Volume 17 Supplement 1, 2010: Proceedings of the 17th International Meeting of Taurine. The full contents of the supplement are available online at http://www.jbiomedsci.com/supplements/17/S1.
- Huxtable RJ: The physiological actions of taurine. Physiol. Rev. 1992, 72: 101-163.PubMedGoogle Scholar
- Sturman JA: Taurine in development. Physiol. Rev. 1993, 73: 119-147.PubMedGoogle Scholar
- Huxtable RJ: Taurine in the central nervous system and the mammalian actions of taurine. Prog. Neurobiol. 1989, 32: 471-533. 10.1016/0301-0082(89)90019-1.View ArticlePubMedGoogle Scholar
- Curtis DR, Watkins JC: The excitation and depression of spinal neurones by structurally related amino acids. J. Neurochem. 1960, 6: 117-141. 10.1111/j.1471-4159.1960.tb13458.x.View ArticlePubMedGoogle Scholar
- Curtis DR, Watkins JC: Analogues of glutamic and gamma-aminobutyric acids having potent action on mammalian neurons. Nature (Lond). 1961, 191: 1010-10.1038/1911010a0.View ArticleGoogle Scholar
- Palackal T, Kujawa M, Moretz RC, Neuringer M, Sturman JA: Laminar analysis of the number of neurons, astrocytes, oligodendrocytes amd microglia in the visual cortex (area 17) of 3-month-old rhesus monkeys fed a human infant soy-protein formula with or without taurine supplementation from birth. Dev. Neurosci. 1991, 13: 20-33. 10.1159/000112137.View ArticlePubMedGoogle Scholar
- Kuriyama K: Taurine as a neuromodulator. Fed. Proc. 1980, 39: 2680-2684.PubMedGoogle Scholar
- Oja SS, Saransaari P: Taurine as osmoregulator and neuromodulator in the brain. Metab Brain Dis. 1996, 11: 153-164. 10.1007/BF02069502.View ArticlePubMedGoogle Scholar
- Saransaari P, Oja SS: Release of GABA and taurine from brain slices. Prog. Neurobiol. 1992, 38: 455-482. 10.1016/0301-0082(92)90046-H.View ArticlePubMedGoogle Scholar
- Moran J, Salazar P, Pasantes-Morales H: Effect of tocopherol and taurine on membrane fluidity of retinal rod outer segments. Exp Eye Res. 1987, 45: 769-776. 10.1016/S0014-4835(87)80094-5.View ArticlePubMedGoogle Scholar
- Okamoto K, Kimura H, Sakai Y: Taurine-induced increase of the Cl-conductance of cerebellar Purkinje cell dendrites in vitro. Brain Res. 1983, 259: 319-323. 10.1016/0006-8993(83)91266-0.View ArticlePubMedGoogle Scholar
- Satoh H, Sperelakis N: Review of some actions of taurine on ion channels of cardiac muscle cells and others. Gen. Pharmacol. 1998, 30: 451-463. 10.1016/S0306-3623(97)00309-1.View ArticlePubMedGoogle Scholar
- Chen WQ, Jin H, Nguyen M, Carr J, Lee YJ, Hsu CC, Faiman MD, Schloss JV, Wu JY: Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons. J Neurosci Res. 2001, 66: 612-619. 10.1002/jnr.10027.View ArticlePubMedGoogle Scholar
- Wade JV, Olson JP, Samson FE, Nelson SR, Pazdernik TL: A possible role for taurine in osmoregulation within the brain. J. Neurochem. 1988, 51: 740-745. 10.1111/j.1471-4159.1988.tb01807.x.View ArticlePubMedGoogle Scholar
- Militante J, Lombardini JB: Age-related retinal degeneration in animal models of aging: Possible involvement of taurine deficiency and oxidative stress. Neurochem Res. 2004, 29: 151-160. 10.1023/B:NERE.0000010444.97959.1b.View ArticlePubMedGoogle Scholar
- Balkan J, Kanbagli O, Hatipoglu A, Kucuk M, Cevikbas U, Toker G, Uysal M: Improving effect of dietary taurine supplementation on the oxidative stress and lipid levels in the plasma, liver and aorta of rabbits fed on a high-cholesterol diet. Biosci Biotechnol Biochem. 2002, 66: 1755-1758. 10.1271/bbb.66.1755.View ArticlePubMedGoogle Scholar
- Takatani T, Takahashi K, Uozumi Y, Shikata E, Yamamoto Y, Ito T, Matsuda T, Schaffer SW, Fujio Y, Azuma J: Taurine inhibits apoptosis by preventing formation of the Apaf-1-caspase-9 apoptosome. Am J Physiol Cell Physiol. 2004, 287: C949-C953. 10.1152/ajpcell.00042.2004.View ArticlePubMedGoogle Scholar
- Paula-Lima AC, Felice GF, Brito-Moreira J, Ferreira TS: Activation of GABAA receptors by taurine and muscimol blocks the neurotoxicity of beta-amyloid in rat hippocampal and cortical neurons. Neuropharmacology. 2005, 49: 1140-1148. 10.1016/j.neuropharm.2005.06.015.View ArticlePubMedGoogle Scholar
- Tadros GM, Khalifa EA, Abdel-Naim BA, Arafa Huntingtons: Neuroprotective effect of taurine in 3-nitropropionic acid-induced experimental animal model of Huntington's disease phenotype. Pharmacol Biochem Behav. 2005, 82: 574-582. 10.1016/j.pbb.2005.10.018.View ArticlePubMedGoogle Scholar
- Ward R, Cirkovic-Vellichovia T, Ledeque F, Tirizitis G, Dubars G, Datla K, Dexter D, Heushling P, Crichton R: Neuroprotection by taurine and taurine analogues. Adv Exp Med Biol. 2006, 583: 299-306. full_text.View ArticlePubMedGoogle Scholar
- Wu JY, Wu H, Jin Y, Wei J, Sha D, Prentice H, Lee HH, Lin CH, Lee YH, Yang LL: Mechanism of Neuroprotective Function of Taurine. Adv Exp Med Biol. 2009, 643: 169-179. full_text.View ArticlePubMedGoogle Scholar
- Metcalf D: The colony stimulating factors discovery, development, and clinical applications. Cancer. 1990, 65: 2185-95. 10.1002/1097-0142(19900515)65:10<2185::AID-CNCR2820651005>3.0.CO;2-4.View ArticlePubMedGoogle Scholar
- Hartung T: Anti-inflammatory effects of granulocyte colony-stimulating factor. Curr Opin Hematol. 1998, 5: 221-225. 10.1097/00062752-199805000-00013.View ArticlePubMedGoogle Scholar
- Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T: Trophic effects of erythropoeitin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res. 1993, 609: 29-35. 10.1016/0006-8993(93)90850-M.View ArticlePubMedGoogle Scholar
- Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S: Neuroprotective effect of granulocyte colonystimulating factor after focal cerebral ischemia. Stroke. 2003, 34: 745-751. 10.1161/01.STR.0000057814.70180.17.View ArticlePubMedGoogle Scholar
- Solaroglu I, Tsubokawa T, Cahill J, Zhang JH: Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat. Neuroscience. 2006, 143: 965-974. 10.1016/j.neuroscience.2006.09.014.PubMed CentralView ArticlePubMedGoogle Scholar
- Meuer K, Pitzer C, Teismann P, Krüger C, Göricke B, Laage R, Lingor P, Peters K, Schlachetzki JC, Kobayashi K, Dietz GP, Weber D, Ferger B, Schäbitz WR, Bach A, Schulz JB, Bähr M, Schneider A, Weishaupt JH: Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson’s disease. J Neurochem. 2006, 97: 675-686. 10.1111/j.1471-4159.2006.03727.x.View ArticlePubMedGoogle Scholar
- Tsai KJ, Tsai YC, Shen CK: G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J Exp Med. 2007, 204: 1273-1280. 10.1084/jem.20062481.PubMed CentralView ArticlePubMedGoogle Scholar
- Hartung T: Anti-inflammatory effects of granulocyte colony-stimulating factor. Curr Opin Hematol. 1998, 5: 221-225. 10.1097/00062752-199805000-00013.View ArticlePubMedGoogle Scholar
- Pan C, Giraldo GS, Prentice H, Wu JY: Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress. J Biomed Sci. 2010, 17 (Suppl 1): S17-10.1186/1423-0127-17-S1-S17.PubMed CentralView ArticlePubMedGoogle Scholar
- Meldrum B, Garthwaite J: Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990, 11: 379-87. 10.1016/0165-6147(90)90184-A.View ArticlePubMedGoogle Scholar
- Leon R, Wu H, Jin Y, Wei J, Buddhala C, Prentice H, Wu J-Y: Protective function of taurine in glutamate-induced apoptosis in cultured neurons. J Neurosci Res. 2009, 87: 1185-1194. 10.1002/jnr.21926.View ArticlePubMedGoogle Scholar
- Hasselblatt M, Jeibmann A, Riesmeier B, Maintz D, Schaitz W-R: Granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor expression in human ischemic stroke. Acta Neuropathol. 2007, 113: 45-51. 10.1007/s00401-006-0152-y.View ArticlePubMedGoogle Scholar
- Lee S-T, Chu K, Jung K-H, Ko S-Y, Kim E-H, Sinn D-I, Lee Y-S, Lo EH, Kim M, Roh J-K: Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res. 2005, 1058: 120-128. 10.1016/j.brainres.2005.07.076.View ArticlePubMedGoogle Scholar
- Yataa K, Matchettc AG, Tsubokawaa T, Tanga J, Kanamarud K, Zhang HJ: Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia–ischemia in rats. Brain Res. 2007, 1145: 227-238. 10.1016/j.brainres.2007.01.144.View ArticleGoogle Scholar
- Chen WF, Jean YH, Sung CS, Wu GJ, Huang SY, Ho JT, Su TM, Wen ZH: Intrathecally injected ranulocyte colony-stimulating factor produced europrotective effects in spinal cord ischemia via the mitogen-activated protein kinase and Akt pathways. Neuroscience. 2008, 153: 31-43. 10.1016/j.neuroscience.2008.01.062.View ArticlePubMedGoogle Scholar
- Aliprandi A, Longoni M, Stanzani L, Tremolizzo L, Vaccaro M, Begni B, Galimberti G, Rosanna G, Ferrarese C: Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake. J Cereb Blood Flow Metab. 2005, 25: 513-519. 10.1038/sj.jcbfm.9600039.View ArticlePubMedGoogle Scholar
- Kaufman RJ: Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002, 110: 1389-1398.PubMed CentralView ArticlePubMedGoogle Scholar
- Ferri KF, Kroemer G: Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001, 3: E255-E263. 10.1038/ncb1101-e255.View ArticlePubMedGoogle Scholar
- Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A: ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007, 129 (z): 1337-1349. 10.1016/j.cell.2007.04.027.View ArticlePubMedGoogle Scholar
- Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000, 403: 98-103. 10.1038/47513.View ArticlePubMedGoogle Scholar
- Idrissi EA, Trenkner E: Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J Neurosci. 1999, 19: 9459-9468.PubMedGoogle Scholar
- Bergamini L, Mutani R, Delsedime M, Durelli L: First clinical experience on the antiepileptic action of taurine. Eur Neurol. 1974, 11: 261-269. 10.1159/000114324.View ArticlePubMedGoogle Scholar
- McCarty MF: The reported clinical utility of taurine in ischemic disorders may reflect a down-regulation of neutrophil activation and adhesion. Med Hypotheses. 1999, 53: 290-299. 10.1054/mehy.1998.0760.View ArticlePubMedGoogle Scholar
- Schäbitz WR: Developing granulocyte-colony stimulating factor for the treatment of stroke: Current status of clinical trials. Stroke. 2006, 37: 1654-10.1161/01.STR.0000227299.62106.0e.View ArticlePubMedGoogle Scholar
- Aliprandi1 A, Longoni M, Stanzani L, Tremolizzo L, Vaccaro M, Begni B, Galimberti G, Garofolo R, Ferrarese C: Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake. J Cereb Blood Flow Metab. 2005, 25: 513-519. 10.1038/sj.jcbfm.9600039.View ArticlePubMedGoogle Scholar
- Maragos WF, Greenamyre JT, Penney JB, Young AB: Glutamate dysfunction in Alzheimer’s disease: an hypothesis. Trends Neurosci. 1987, 10: 65-68. 10.1016/0166-2236(87)90025-7.View ArticleGoogle Scholar
- Greenamyre JT: Glutamate-dopamine interactions in the basal ganglia relationship to Parkinson’s disease. J Neural Transm Gen Sect. 1993, 91: 255-269. 10.1007/BF01245235.View ArticlePubMedGoogle Scholar
- Yu Z, Luo H, Fu W, Mattson MP: The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp. Neurol. 1999, 155: 302-314. 10.1006/exnr.1998.7002.View ArticlePubMedGoogle Scholar
- Kitao Y, Ozawa K, Miyazaki M, Tamatani M, Kobayashi T, Yanagi H, Okabe M, Ikawa M, Yamashima T, Stern DM, Hori O, Ogawa S: Expression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity. J. Clin. Invest. 2001, 108 (z): 1439-1450.PubMed CentralView ArticlePubMedGoogle Scholar
- Sokka AL, Putkonen N, Mudo G, Pryazhnikov E, Reijonen S, Khiroug L, Belluardo N, Lindholm D, Korhonen L: Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain. J Neurosci. 2007, 27: 901-908. 10.1523/JNEUROSCI.4289-06.2007.View ArticlePubMedGoogle Scholar
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