[en] Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, Germany. heneka@uni-bonn.de
Feinstein, D L
Galea, Elena; Department of Anesthesiology, Neuroanesthesia Res., Univ. I., Chicago, IL, United States
Gleichmann, Marc; Department of Neurology, University of Tübingen, Tübingen, Germany
Wüllner, Ullrich; Department of Neurology, University of Bonn, Bonn, Germany
Klockgether, Thomas; Department of Neurology, University of Bonn, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 430, B7) and a grant from the National Multiple Sclerosis Society (to D.L.F.).
Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:1976;248-254.
Braissant O., Foufelle F., Scotto C., Dauca M., Wahli W. Differential expression of peroxisome proliferator-activated receptors PPARs: tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 137:1996;354-366.
Bredt D.S., Snyder S.H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A. 87:1990;682-685.
Chester A.H., Borland J.A., Buttery L.D., Mitchell J.A., Cunningham D.A., Hafizi S., Hoare G.S., Springall D.R., Polak J.M., Yacoub M.H. Induction of nitric oxide synthase in human vascular smooth muscle: interactions between pro-inflammatory cytokines. Cardiovasc. Res. 38:1998;814-821.
Colville N.P., Qureshi S.S., Willis D., Willoughby D.A. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J. Immunol. 161:1998;978-984.
Cotman C.W. Apoptosis decision cascades and neuronal degeneration in Alzheimer's Disease. Neurobiol. Aging. 19:1998;S29-S32.
Dawson T.M., Dawson V.L. ADP ribosylation as a mechanism for the action of nitric oxide in the nervous system. New Horiz. 3:1995;85-92.
Dawson T.M., Dawson V.L., Snyder S.H. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann. Neurol. 32:1992;297-311. see comments.
D'Mello S.R., Galli C., Ciotti T., Calissano P. Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. Proc. Natl. Acad. Sci. U.S.A. 90:1993;10989-10993.
D'Mello S.R., Anelli R., Calissano P. Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons. Exp. Cell Res. 211:1994;332-338.
Du Y., Bales K.R., Dodel R.C., Hamilton B.E., Horn J.W., Czilli D.L., Simmons L.K., Ni B., Paul S.M. Activation of a caspase-3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc. Natl. Acad. Sci. U.S.A. 94:1997;11657-11662.
Du Y., Dodel R.C., Bales K.R., Jemmerson R., Hamilton B.E., Paul S.M. Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons. J. Neurochem. 69:1997;1382-1388.
Forman B.M., Tontonoz P., Chen J., Brun R.P., Spiegelman B.M., Evans R.M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 83:1995;803-812.
Gabriel C., Camins A., Sureda F.X., Aquirre L., Escubedo E., Pallas M., Camarasa J. Determination of nitric oxide generation in mammalian neurons using dichlorofluorescein diacetate and flow cytometry. J. Pharmacol. Toxicol. Methods. 38:1997;93-98.
Galea E., Feinstein D.L., Reis D.J. Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc. Natl. Acad. Sci. U.S.A. 89:1992;10945-10949.
Galea E., Reis D.J., Feinstein D.L. Cloning and expression of inducible nitric oxide synthase from rat astrocytes. J. Neurosci. Res. 37:1994;406-414.
Galea, E., Golanov, E.V., Feinstein, D.L., Kobylarz, K., Glickstein, S.B., Reis, D.J., 1999. Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia. Am. J. Physiol., H2035-H2045.
Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 14:1991;60-67.
Gunasekar P.G., Kanthasamy A.G., Borowitz J.L., Isom G.E. Monitoring intracellular nitric oxide formation by dichlorofluorescein in neuronal cells. J. Neurosci. Methods. 61:1995;15-21.
Heneka M.T., Loschmann P.A., Gleichmann M., Weller M., Schulz J.B., Wullner U., Klockgether T. Induction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal PC12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide. J. Neurochem. 71:1998;88-94.
Heneka M.T., Schmidlin A., Wiesinger H. Induction of argininosuccinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants. J. Cereb. Blood Flow Metab. 19:1999;898-907.
Hibbs-JB J., Taintor R.R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deaminase and imino nitrogen oxidation to nitrite. Science. 235:1987;473-476.
Hu J., Van E.L. S100 beta induces apoptotic cell death in cultured astrocytes via a nitric oxide-dependent pathway. Biochim. Biophys. Acta. 1313:1996;239-245.
Hu J., Akama K.T., Krafft G.A., Chromy B.A., Van E.L. Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res. 785:1998;195-206.
Ii M., Sunamoto M., Ohnishi K., Ichimori Y. Beta-amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. Brain Res. 720:1996;93-100.
Jiang C., Ting A.T., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 391:1998;82-86.
Kifle Y., Monnier J., Chesrown S.E., Raizada M.K., Nick H.S. Regulation of the manganese superoxide dismutase and inducible nitric oxide synthase gene in rat neuronal and glial cells. J. Neurochem. 66:1996;2128-2135.
Kitamura Y., Shimohama S., Koike H., Kakimura J., Matsuoka Y., Nomura Y., Gebicke H.P., Taniguchi T. Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's Disease brains. Biochem. Biophys. Res. Commun. 254:1999;582-586.
Kliewer S.A., Lenhard J.M., Willson T.M., Patel I., Morris D.C., Lehmann J.M. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 83:1995;813-819.
Kliewer S.A., Sundseth S.S., Jones S.A., Brown P.J., Wisely G.B., Koble C.S., Devchand P., Wahli W., Willson T.M., Lenhard J.M., Lehmann J.M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. U.S.A. 94:1997;4318-4323.
Krey G., Braissant O., Horset F., Kalkhoven E., Perroud M., Parker M.G., Wahli W. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol. 11:1997;779-791.
Lafon C.M., Pietri S., Culcasi M., Bockaert J. NMDA-dependent superoxide production and neurotoxicity. Nature. 364:1993;535-537.
Lehmann J.M., Lenhard J.M., Oliver B.B., Ringold G.M., Kliewer S.A. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 272:1997;3406-3410.
Leist M., Volbracht C., Kuhnle S., Fava E., Ferrando M.E., Nicotera P. Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Mol. Med. 3:1997;750-764.
Lemberger T., Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12:1996;335-363.
Loo D.T., Copani A., Pike C.J., Whittemore E.R., Walencewicz A.J., Cotman C.W. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc. Natl. Acad. Sci. U.S.A. 90:1993;7951-7955.
Lowenstein C.J., Glatt C.S., Bredt D.S., Snyder S.H. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc. Natl. Acad. Sci. U.S.A. 89:1992;6711-6715.
Marini A.M., Paul S.M. N-methyl-D-aspartate receptor-mediated neuroprotection in cerebellar granule cells requires new RNA and protein synthesis. Proc. Natl. Acad. Sci. U.S.A. 89:1992;6555-6559.
Marks N., Berg M.J., Guidotti A., Saito M. Activation of caspase-3 and apoptosis in cerebellar granule cells. J. Neurosci. Res. 52:1998;334-341.
McGeer P.L., McGeer E.G. Glial cell reactions in neurodegenerative diseases: pathophysiology and therapeutic interventions. Alzheimer Dis. Assoc. Disord. 12(2):1998;S1-S6. Suppl.
McGeer P.L., Schulzer M., McGeer E.G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's Disease: a review of 17 epidemiologic studies. Neurology. 47:1996;425-432. see comments.
Minc G.D., Tsarfaty I., Schwartz J.P. Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine. Br. J. Pharmacol. 112:1994;720-722.
Minc G.D., Yadid G., Tsarfaty I., Resau J.H., Schwartz J.P. Expression of the inducible nitric oxide synthase by neurons following exposure to endotoxin and cytokine. J. Neurochem. 66:1994;1504-1509.
Moncada S., Higgs A. The L-arginine-nitric oxide pathway. New Engl. J. Med. 329:1993;2002-2012.
Nicoletti F., Wroblewski J.T., Novelli A., Alho H., Guidotti A., Costa E. The activation of inositol phospholipid metabolism as a signal-transducing system for excitatory amino acids in primary cultures of cerebellar granule cells. J. Neurosci. 6:1986;1905-1911.
Pasinetti G.M., Aisen P.S. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's Disease brain. Neuroscience. 87:1998;319-324.
Petrova T.V., Akama K.T., Van Eldik L.J. Cyclopentanone prostaglandins suppress activation of microglia: downregulation of inducible nitric oxide synthase by 15-deoxy-Δ12,14 prostaglandin J2. Proc. Natl. Acad. Sci. U.S.A. 96:1999;4668.
Pollard H., Charriaut M.C., Cantagrel S., Represa A., Robain O., Moreau J., Ben A.Y. Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience. 63:1994;7-18.
Ricote M., Li A.C., Willson T.M., Kelly C.J., Glass C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 391:1998;79-82.
Sarih M., Souvannavong V., Adam A. Nitric oxide synthase induces macrophage death by apoptosis. Biochem. Biophys. Res. Commun. 191:1993;503-508.
Sato I., Kim Y., Himi T., Murota S. Induction of calcium-independent nitric oxide synthase activity in cultured cerebellar granule neurons. Neurosci. Lett. 184:1995;145-148.
Sato I., Himi T., Murota S. Lipopolysaccharide-induced nitric oxide synthase activity in cultured cerebellar granule neurons. Neurosci. Lett. 205:1996;45-48.
Schmidlin A., Wiesinger H. Argininosuccinate synthetase: localization in astrocytes and role in the production of glial nitric oxide. Glia. 24:1998;428-436.
Schulz J.B., Weller M., Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons: a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J. Neurosci. 16:1996;4696-4706.
Simmons M.L., Murphy S. Induction of nitric oxide synthase in glial cells. J. Neurochem. 59:1992;897-905.
Skaper S.D., Facci L., Leon A. Inflammatory mediator stimulation of astrocytes and meningeal fibroblasts induces neuronal degeneration via the nitridergic pathway. J. Neurochem. 64:1995;266-276.
Smith M.A., Richey H.P., Sayre L.M., Beckman J.S., Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's Disease. J. Neurosci. 17:1997;2653-2657.
Stuehr D.J., Nathan C.F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 169:1989;1543-1555.
Stuehr D.J., Gross S.S., Sakuma I., Levi R., Nathan C.F. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J. Exp. Med. 169:1989;1011-1020.
Uehara T., Kikuchi Y., Nomura Y. Caspase activation accompanying cytochrome c release from mitochondria is possibly involved in nitric oxide-induced neuronal apoptosis in SH-SY5Y cells. J. Neurochem. 72:1999;196-205.
Vodovotz Y., Lucia M.S., Flanders K.C., Chesler L., Xie Q.W., Smith T.W., Weidner J., Mumford R., Webber R., Nathan C., Roberts A.B., Lippa C.F., Sporn M.B. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's Disease. J. Exp. Med. 184:1996;1425-1433.
Weller M., Marini A.M., Paul S.M. Niacinamide blocks 3-acetylpyridine toxicity of cerebellar granule cells in vitro. Brain Res. 594:1992;160-164.
Willson T.M., Lehmann J.M., Kliewer S.A. Discovery of ligands for the nuclear peroxisome proliferator-activated receptors. Ann. N.Y. Acad. Sci. 804:1996;276-283.
Yu K., Bayona W., Kallen C.B., Harding H.P., Ravera C.P., McMahon G., Brown M., Lazar M.A. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 270:1995;23975-23983.
