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Aurintricarboxylic Acid Prevents GLUR2 Mrna Down-Regulation

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Aurintricarboxylic Acid Prevents GLUR2 Mrna Down-Regulation Proc. Natl. Acad. Sci. USA Vol. 95, pp. 7115–7120, June 1998 Neurobiology Aurintricarboxylic acid prevents GLUR2 mRNA down-regulation and delayed neurodegeneration in hippocampal CA1 neurons of gerbil after global ischemia (transient ischemiaydegenerationyAMPA receptorsyGluR2ymRNA expressionyexcitotoxicity) ELEONORA M. ARONICA*, JAN A. GORTER*, SONJA GROOMS†,JOHN A. KESSLER†‡,MICHAEL V. L. BENNETT†, R. SUZANNE ZUKIN†, AND DANIEL M. ROSENBAUM‡§ Departments of †Neuroscience and ‡Neurology, Albert Einstein College of Medicine, Bronx, NY 10461 Contributed by Michael V. L. Bennett, March 4, 1998 ABSTRACT Aurintricarboxylic acid (ATA), an inhibitor 5-methyl-4-isoxazolepropionic acid (AMPA) receptors lacking of endonuclease activity and other protein–nucleic acid inter- the GluR2 subunit have markedly increased Ca21 permeability actions, blocks apoptosis in several cell types and prevents (for review, see ref. 13), down-regulation of GluR2 mRNA delayed death of hippocampal pyramidal CA1 neurons in- while GluR1 mRNA levels are essentially unchanged would duced by transient global ischemia. Global ischemia in rats lead to increased formation of Ca21 permeable AMPA recep- and gerbils induces down-regulation of GluR2 mRNA and tors and increased toxicity of endogenous glutamate (the increased a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic GluR2 hypothesis, refs. 14 and 15). In agreement with this 1 acid (AMPA)-induced Ca2 influx in CA1 before neurodegen- prediction, postischemic CA1 neurons exhibit greater AMPA- eration. This result and neuroprotection by antagonists of induced Ca21 influx than do control CA1 neurons, and this AMPA receptors suggests that formation of AMPA receptors increase in Ca21 influx occurs before obvious degeneration 1 lacking GluR2, and therefore Ca2 permeable, leads to exces- (5). The AMPA receptor-mediated excitatory post-synaptic 1 sive Ca2 influx in response to endogenous glutamate; the currents in postischemic CA1 neurons show greater sensitivity resulting delayed neuronal death in CA1 exhibits many char- to block by 1-naphthyl-acetyl-spermine (16), a channel blocker acteristics of apoptosis. In this study, we examined the effects selective for Ca21 permeable AMPA receptors (17, 18). The of ATA on expression of mRNAs encoding glutamate receptor excitatory post-synaptic currents also are increased in dura- subunits in gerbil hippocampus after global ischemia. Admin- tion, but this change has no obvious relation to the change in istration of ATA by injection into the right cerebral ventricle GluR2 expression. 1 h before (but not6hafter) bilateral carotid occlusion An additional foundation of the GluR2 hypothesis is the prevented the ischemia-induced decrease in GluR2 mRNA observation that antagonists of AMPA and kainate receptors expression and the delayed neurodegeneration. These findings [but not of N-methyl-D-aspartate (NMDA) receptors] are suggest that ATA is neuroprotective in ischemia by blocking effective in preventing or greatly delaying hippocampal de- the transcriptional changes leading to down-regulation of generation after global ischemia, even when given 16 to 24 h GluR2, rather than by simply blocking endonucleases, which after reperfusion (19–24; for review, see ref. 25). Neuropro- 1 presumably act later after Ca2 influx initiates apoptosis. tective doses of AMPA antagonists given at the time of 1 Maintaining formation of Ca2 impermeable, GluR2 contain- reperfusion or 8 h later do not prevent down-regulation of ing AMPA receptors could prevent delayed death of CA1 GluR2 mRNA, suggesting that the protection results from neurons after transient global ischemia, and block of GluR2 blockade of Ca21 permeable receptors rather than from down-regulation may provide a further strategy for neuro- prevention of their formation (10). protection. The mechanism of delayed neuronal death after ischemia remains somewhat controversial. There are alterations in gene Transient forebrain or global ischemia, induced in animals or and protein expression and fragmentation of DNA consistent occurring in humans as a result of cardiac arrest, is followed by with apoptosis (26–30), but others fail to find the characteristic delayed neurodegeneration in specific neuronal populations. morphological changes of this process (31). Pyramidal neurons of the hippocampal CA1 are particularly Down-regulation of GluR2 also is thought to play a role in vulnerable (for review, see ref. 1). During a brief episode of delayed neurodegeneration after kainic acid-induced status global ischemia (5–10 min) in rat or gerbil, extracellular epilepticus; in this paradigm, the CA3 region exhibits delayed concentrations of glutamate and K1 and intracellular levels of neurodegeneration and selective down-regulation of GluR2 free Ca21 rise throughout the forebrain, and neurons depo- (32). Furthermore, hippocampal neurons subject to oxygen larize and become inexcitable. However, within minutes after and glucose deprivation in culture show increased Ca21 per- reperfusion, the extracellular milieu is restored, cytoplasmic meability of AMPA receptors and greater sensitivity to kainate Ca21 returns to resting levels, and neurons can again generate excitotoxicity (33). action potentials (2–4; see ref. 5). In the hippocampal CA1, The present study was undertaken to investigate further the this recovery is transient and after several days is followed by molecular mechanisms underlying ischemia-induced neuronal extensive degeneration of pyramidal neurons (6–8). cell death. By using the two-vessel occlusion model in gerbils, Global ischemia leads to specific down-regulation of GluR2 we examined the effect of aurintricarboxylic acid (ATA) on mRNA localized to the vulnerable CA1 before histologically a detectable cell death (5, 9–12). Because -amino-3-hydroxy- Abbreviations: ATA, aurintricarboxylic acid; AMPA, a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid; i.c.v., intracerebroventricu- The publication costs of this article were defrayed in part by page charge lar; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline; NMDA, N-methyl-D-aspartate. payment. This article must therefore be hereby marked ‘‘advertisement’’ in *Present address: Instituut voor Neurobiologie, Kruislaan 320, 1098 accordance with 18 U.S.C. §1734 solely to indicate this fact. SM Amsterdam, The Netherlands. © 1998 by The National Academy of Sciences 0027-8424y98y957115-6$2.00y0 §To whom reprint requests should be addressed. e-mail: drosenba@ PNAS is available online at http:yywww.pnas.org. aecom.yu.edu. 7115 Downloaded by guest on September 24, 2021 7116 Neurobiology: Aronica et al. Proc. Natl. Acad. Sci. USA 95 (1998) changes in AMPA- and NMDA-receptor gene expression Histological Analysis. Neuronal cell loss in the hippocampus induced by global ischemia. ATA administered 1 h before was assessed by histological examination of coronal sections. induction of global ischemia prevents the delayed neuronal cell Thionin staining was performed before in situ hybridization on death in the hippocampal CA1 (measured by spectrin break- air dried sections from all of the animals killed at 48 h. Coronal down, ref. 34; and by histologic examination, ref. 30). ATA also blocks from brains of animals killed7dafterischemia were reduces delayed neurodegeneration after retinal ischemia (35). embedded in paraffin, sectioned at 7 mm, and stained with ATA blocks apoptosis in PC12 cells and neuronal cultures (36, hematoxylinyeosin. 37) and can act as an endonuclease inhibitor (38). ATA binds In Situ Hybridization. [35S]UTP-labeled RNA probes were nonspecifically to nucleic acids as well as proteins and can transcribed from the cDNAs for the GluR1 and GluR2 inhibit other protein–nucleic acid interactions, such as tran- AMPA-receptor subunits and for the NR1011 NMDA receptor scription and protein synthesis (e.g., refs. 39–41). ATA ap- subunit. cDNA templates were incubated with the appropriate parently can act as a competitive antagonist at NMDA recep- polymerase (T7 for GluR1–2; T3 for NR1) and labeled and tors (42), but, as noted above, NMDA antagonists appear not unlabeled nucleotides (1 h, 37°C), using a Stratagene tran- to be neuroprotective in global ischemia (10, 21). scription kit. RNA probes were purified by phenolychloroform We show here that ATA sufficient to protect CA1 neurons extraction. against delayed neurodegeneration after global ischemia pre- Glutamate receptor mRNA expression was measured by in vents the down-regulation of GluR2 mRNA. Moreover, ATA situ hybridization on sections of control and postischemic administered6hafterreperfusion neither prevents down- gerbil brains by a modification of Pellegrini-Giampietro et al. regulation of GluR2 nor provides neuroprotection. These (45). In brief, coronal sections (20 mm) of frozen brains from results suggest that ATA given before the insult protects by sham-operated control (n 5 4 with saline injection and n 5 4 blocking the transcriptional changes that lead to GluR2 down- without) and 48-h postischemic gerbils treated with saline (n 5 regulation and only indirectly prevents the later changes in 8) or ATA (n 5 7) were hybridized with [35S]UTP-labeled gene expression that immediately precede cell death (30, 43, RNA probes directed against the GluR1, GluR2, and NR1 44). These results provide additional support for the hypothesis subunit mRNAs. Before application of RNA probe, sections 1 that reduction in GluR2 expression and formation of Ca2 were subjected to acetylation and incubated for2hat50°C permeable AMPA receptors play a
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