doi: 10.1161/01.STR.0000016404.14407.77
(Stroke. 2002;33:1698.)
© 2002 American Heart Association, Inc.
Original Contributions |
[3H]Muscimol Binding to 
-Aminobutyric AcidA Receptors Is Upregulated in CA1 Neurons of the Gerbil Hippocampus in the Ischemia-Tolerant State
From the Department of Neuropathology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany.
Correspondence to Clemens Sommer, MD, Laboratory of Neuropathology, Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. E-mail clemens.sommer{at}medizin.uni-ulm.de
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Background and Purpose— Excitotoxic activation of glutamate receptors is currently thought to play a pivotal role in delayed neuronal death (DND) of highly vulnerable CA1 neurons in the gerbil hippocampus after transient global ischemia. Postischemic degeneration of these neurons can be prevented by "preconditioning" with a short sublethal ischemic stimulus. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of ligand binding to excitatory glutamate and/or inhibitory
-aminobutyric acid (GABA)A receptors compared with ischemia severe enough to induce DND.
Methods— With the use of quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801 and [3H]
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-D-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABAA receptors in hippocampal subfields CA1, CA3, and the dentate gyrus were analyzed in 2 experimental paradigms. Gerbils were subjected to (1) a 5-minute ischemic period resulting in DND of CA1 neurons and (2) a 2.5-minute period of ischemia mediating tolerance induction.
Results— [3H]MK-801 and [3H]AMPA binding values to excitatory NMDA and AMPA receptors showed a delayed decrease in relatively ischemia-resistant CA3 and dentate gyrus despite maintained neuronal cell density. [3H]Muscimol binding to GABAA receptors in CA1 neurons was transiently but significantly increased after preconditioning but not after global ischemia with consecutive neuronal death.
Conclusions— Downregulation of ligand binding to glutamate receptors in relatively ischemia-resistant CA3 and dentate gyrus neurons destined to survive suggests marked synaptic reorganization processes despite maintained structural integrity. More importantly, upregulation of binding to inhibitory GABAA receptors in the hippocampus indicates a relative shift between inhibitory and excitatory neurotransmission that we suggest may participate in endogenous postischemic neuroprotection.
Key Words: autoradiography • excitotoxicity • ischemia • neuroprotection • receptors, AMPA • receptors, GABA-A • gerbils
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Transient global ischemia of only 5 minutes’ duration causes selective and delayed neuronal death (DND) of hippocampal CA1 neurons 3 to 4 days after recirculation.1 According to current concepts, excitotoxic activation of various glutamate receptors is thought to play a key role in the induction of subsequent neuronal death (for review, see Lee and colleagues2). DND can be prevented by a great number of preconditioning stimuli such as brief ischemic periods, spreading depression, potassium-induced depolarization, chemical inhibition of oxidative phosphorylation, and exposure to excitotoxins and cytokines (for review, see Dawson and Dawson3). The molecular basis of ischemia tolerance induction, however, is not yet understood. Both DND and tolerance induction can be prevented by pharmacological blockade of various excitatory glutamate receptors.4–6 On the other hand, pharmacological stimulation of the
-aminobutyric acid (GABA)-ergic system has been shown to protect vulnerable CA1 neurons against ischemic damage (for review, see Schwartz-Bloom and Sah7). Therefore, besides the induction of several genes coding for proteins thought to be involved in neuroprotective mechanisms, 8 changes in the postischemic expression, abundance, and function of neurotransmitter receptors may also contribute to the acquired ischemia resistance of hippocampal CA1 neurons.
The present study was designed to address the question of whether ligand binding to excitatory and/or inhibitory neurotransmitter receptors is specifically regulated after a 2.5-minute period of ischemia, usually used to induce ischemia tolerance. Therefore, postischemic receptor binding activities of [3H]MK-801 and [3H]-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-D-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABAA receptors were analyzed after both 2.5 and 5 minutes of global ischemia in hippocampal subfields CA1, CA3, and the dentate gyrus (DG).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animal Experiments
Experiments were performed on adult male Mongolian gerbils (Meriones unguiculatus; weight, 70 to 80 g) obtained from Charles River Deutschland (Sulzfeld, Germany). Animals had free access to food and water before experiments. Gerbils were subjected to transient forebrain ischemia by bilateral occlusion of the common carotid artery. Ischemia was induced according to the protocol of Kirino and colleagues.9 Anesthesia was achieved with a mixture of 30% O2, 70% N2O, and 1.5% halothane. Two experimental groups of animals were investigated. One group was subjected to global ischemia of 5 minutes’ duration, resulting in DND of hippocampal CA1 neurons. A second group was subjected to a short ischemic period of 2.5 minutes, which we normally use for ischemia tolerance induction.10,11 Control gerbils (n=8) were subjected to a sham operation consisting of anesthesia and all surgical procedures, except clamping of the carotid arteries. At the determined end point of the experiment, ie, 30 minutes, 8 hours, 24 hours, 48 hours, and 96 hours after reperfusion (n=4 to 5 per time point), animals were decapitated, and brains were rapidly removed, frozen in isopentane at -30°C for 10 minutes, and stored at -80°C until analysis. Coronal cryostat sections of 12-µm thickness were serially cut at -20°C at the level of the dorsal hippocampus and mounted on triethoxysilylpropylamine-coated slides. All animal procedures were performed according to the guidelines of the German animal protection law.
Neuropathological Evaluation
Neuronal densities of hippocampal CA1 and CA3 pyramidal layers as well as of the DG granule cell layer were quantitatively assessed at 48 and 96 hours after reperfusion and in sham-operated animals by labeling neurons with a monoclonal antibody against the neuronal marker protein NeuN (dilution 1:2000), as previously described.11 Briefly, immunoreactivity was visualized with the use of the avidin-biotin complex method (Vectastain, Vector Laboratories). Sections were developed in 0.02% diaminobenzidine with 0.02% hydrogen peroxide. The reaction product was intensified by addition of 0.02% cobalt chloride and nickel ammonium sulfate. Hippocampal subfields CA1, CA3, and DG of both hemispheres were scanned at a magnification of x300. Two sets of 3 adjacent regions per area per hemisphere were recorded, averaged, and expressed as mean cell number per square millimeter ("neuronal density"). All data were statistically analyzed with the use of the general statistics module of Analyze-it for Microsoft Excel (Analyze-it Software, Ltd). Values were expressed as mean±SEM. Significant group effects were confirmed by ANOVA and Bonferroni error protection, with a significance level at P<0.05.
Receptor Autoradiography
Quantitative in vitro receptor autoradiography studies were performed with the use of [3H]MK-801, [3H]AMPA, and [3H]muscimol for labeling of NMDA, AMPA, and GABAA receptors, respectively.12–15 Ligands were purchased from NEN Life Science Products Inc. Labeling and incubation procedures for the different binding sites were performed according to protocols of Zilles and colleagues.16 Briefly, incubation with [3H]MK-801, [3H]AMPA, and [3H]muscimol was always preceded by a preincubation period with the respective buffer to remove endogenous ligands. For demonstrating the maximal binding of [3H]MK-801 to NMDA receptors, the binding assay was performed in a magnesium- and zinc-free solution (50 mmol/L Tris-HCl buffer, pH 7.2) and in the presence of 30 µmol/L glycine and 50 µmol/L spermidine with 5 nmol/L [3H]MK-801 (specific activity, 21.7 Ci/mmol) at 22°C for 60 minutes. Incubation was terminated by washing with 2x 5 minutes of cold buffer and 2 seconds of H2O. AMPA receptors were labeled with 10 nmol/L [3H]AMPA (specific activity, 42.2. Ci/mmol) in 50 mmol/L Tris-acetate buffer (pH 7.2, containing 100 mmol/L KSCN) for 45 minutes at 4°C. Termination of the incubation was done with 3x 4-second rinses with cold buffer and postfixation with 2x 2-second rinses with acetone/glutaraldehyde solution. GABAA receptors were incubated with 3 nmol/L [3H]muscimol (50 mmol/L Tris-citrate buffer, pH 7.0) for 40 minutes at 4°C. Incubation was terminated with 3x 4-second rinses in cold buffer. Unspecific binding was determined by coincubation of alternating sections with labeled ligands and an excess of appropriate unlabeled competitor. After the final rinsing procedure, slides were carefully dried in either a stream of cool ([3H]MK-801 and [3H]muscimol) or hot ([3H]AMPA) air. Air-dried, tritium-labeled sections were coexposed with [3H]plastic standards (Microscales; Amersham) and brain-paste standards to a [3H]-sensitive film (Hyperfilm; Amersham) for 4 ([3H]AMPA) or 5 weeks ([3H]MK-801 and [3H]muscimol), respectively. Then autoradiographies were scanned in equal light conditions with a DMC video camera (Polaroid) and digitized with the AIS image analysis system (Imaging Research Inc). Gray value images of the coexposed plastic standards were used to compute a nonlinear calibration curve, which defined the relationship between gray values in the autoradiographs and concentrations of radioactivity. Plastic standards were calibrated to tissue standards with known concentration of radioactivity. Final values are expressed as femtomoles per milligram tissue (mean±SEM).
Quantitative analysis of radioactivity was performed in hippocampal subfields CA1 and CA3 within the dendritic strata oriens and radiatum as well as in the pyramidal cell layer. In the DG, ligand binding was analyzed in the dendritic stratum moleculare and in the granule cell layer. To this end, the respective region was marked on the monitor, and the gray values were automatically assessed by the imaging software. In all cases, nonspecific binding was just above the background labeling or not visible at all. Therefore, background density could be used as an estimate of nonspecific binding and subtracted from total binding.
Statistical analysis was performed with the general statistics module of Analyze-it for Microsoft Excel (Analyze-it Software, Ltd). For each ligand, reperfusion time point, and hippocampal region, mean concentration values were calculated. Significant group effects were confirmed by ANOVA and Bonferroni error protection, with a significance level at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Neuropathological Evaluation
Immunohistochemical analysis of NeuN-stained neurons in hippocampal subfields CA1, CA3, and DG at 48 and 96 hours after 5 minutes of global ischemia yielded a significant reduction of neuronal cell density only in the ischemic CA1 subfield after 96 hours compared with control gerbils (Table). A preconditioning 2.5-minute period of ischemia did not result in significant changes in neuronal cell density in hippocampal subfields CA1, CA3, and DG (Table).
|
Receptor Autoradiography
[3H]MK-801 Binding
5-Minute Ischemia
In control gerbils, highest hippocampal [3H]MK-801 binding values were present in stratum radiatum and stratum oriens of CA1, followed by stratum radiatum and stratum oriens of CA3, stratum moleculare of the dentate gyrus (DG), and the pyramidal and granule cell layer, respectively (Figure 1). This distribution pattern is in agreement with other studies investigating [3H]MK-801 binding in hippocampi of gerbils and rats.12,13 After global ischemia of 5 minutes’ duration, binding values of [3H]MK-801 in CA1 were maintained up to 24 hours, followed by a continuous and progressive reduction in all layers up to 39% of control values (Figure 2). In CA3, [3H]MK-801 binding density was transiently decreased in dendritic layers at 48 hours (Figure 2). In the DG, a transient decrease of [3H]MK-801 binding values was also detectable at 48 hours (Figure 2).
|
|
2.5-Minute Ischemia
A preconditioning 2.5-minute period of ischemia caused no significant reduction of [3H]MK-801 binding values up to 96 hours after reperfusion in CA1 (Figure 2). In the CA3 subfield, [3H]MK-801 binding density in the pyramidal cell layer decreased between 30 minutes and 96 hours (Figure 2). [3H]MK-801 binding values were also transiently decreased in the granule cell layer of the DG between 24 and 96 hours (Figure 2).
[3H]AMPA Binding
5-Minute Ischemia
In control gerbils, highest binding values for [3H]AMPA were detected in stratum pyramidale of CA1 and CA3 and in stratum granulare of the DG compared with dendritic layers of these hippocampal subfields (Figure 1), a regional distribution pattern corresponding to that published for rat hippocampus.14 An ischemic period of 5 minutes’ duration caused a significant reduction of [3H]AMPA binding values as early as 30 minutes after reperfusion in stratum radiatum of CA1, followed by a recovery at 24 and 48 hours and a secondary decline at 96 hours (Figure 3). In strata oriens and pyramidale of CA1, [3H]AMPA binding densities were also significantly reduced at 96 hours after reperfusion. In stratum pyramidale of CA3, a delayed and significant reduction of [3H]AMPA binding values was detected at 24 hours and at all later time points investigated (Figure 3). [3H]AMPA binding densities were also significantly lowered in strata moleculare and granulare of the DG at 96 hours (Figure 3).
|
2.5-Minute Ischemia
After an ischemic period of 2.5 minutes, a significant increase of [3H]AMPA binding was present at 24 hours throughout all layers of CA1 up to 171% of binding values in control gerbils and was followed by a continuous decrease to minimal 69% at 96 hours after reperfusion, which was not significant (Figure 3). In the CA3 subfield, [3H]AMPA binding was unchanged up to 48 hours and decreased to minimal 64% of binding values in control animals 96 hours after recirculation (Figure 3). Similarly, [3H]AMPA binding densities in the DG decreased significantly first at 96 hours of reperfusion (Figure 3).
[3H]Muscimol Binding
5-Minute Ischemia
In accordance with the literature, binding intensity of [3H]muscimol was strongest in CA1, followed by DG and CA3 (Figures 4 and 5). 12,15,17 In CA1, postischemic binding values were not significantly altered at any time point investigated. In CA3 and DG, [3H]muscimol binding was also not significantly changed (Figures 4 and 5).
|
|
2.5-Minute Ischemia
Apart from stratum pyramidale at 30 minutes after recirculation, a preconditioning ischemic period of 2.5 minutes’ duration induced an increase of [3H]muscimol binding in CA1 throughout all layers between 30 minutes and 96 hours, which was significant between 8 and 48 hours (Figures 4 and 5). Four days after recirculation, [3H]muscimol binding in CA1 was still elevated (approximately 160% of control values). In CA3, [3H]muscimol was already significantly increased at 30 minutes, reached peak levels at 24 hours, and then decreased to 128% of control values at 96 hours after reperfusion (Figures 4 and 5). A marked increase of [3H]muscimol binding activity was also present in the DG between 30 minutes and 96 hours of reperfusion, with peak levels up to 234% of control levels at 8 hours (Figures 4 and 5).
Ratio Between Ligand Binding to Excitatory and Inhibitory Receptors
To obtain an impression of the balance between ligand binding to excitatory and inhibitory receptors in postischemic CA1, the ratio of binding values in all layers (both dendritic layers and pyramidal layer) of [3H]MK-801 plus [3H]AMPA versus [3H]muscimol, respectively, was calculated (Figure 6). After global ischemia of 5 minutes’ duration, the ratio remained constant up to 24 hours after reperfusion. A shift toward [3H]muscimol binding was first seen at 48 hours. In contrast, 2.5 minutes of ischemia shifted the ratio toward [3H]muscimol binding at 30 minutes and more markedly at 8 hours after reperfusion, persisting at this level up to 96 hours.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Our present study demonstrates for the first time that a short 2.5-minute period of ischemia usually used to induce ischemia tolerance is associated with an increase of [3H]muscimol binding to GABAA receptors in hippocampal CA1 neurons (Figure 4). Global ischemia of 5 minutes’ duration and consecutive DND of CA1 principal neurons fails to enhance ligand binding to these inhibitory receptors (Figures 4 and 5). Selective upregulation after 2.5 minutes of [3H]muscimol binding also occurs in DG and CA3 (Figures 4 and 5). These data suggest that activation of the GABAergic system may be an essential component in endogenous ischemia resistance. These findings are in accord with pharmacological neuroprotection of vulnerable CA1 neurons against DND after 5 minutes of global ischemia in gerbils by exogenous application of substances activating the GABAergic system, ie, GABAA receptor agonists,18 GABAA receptor modulators,19–24 or GABA reuptake inhibitors.25,26 Since the phenomenon of ischemic preconditioning has also been observed in organs other than the brain, eg, the heart,27 it would be unreasonable to assume that there are identical molecular mechanisms mediating tolerance induction. Although NMDA receptors have been shown to play a crucial role in preconditioning in the brain,6 the heart lacks these receptors. Similarly, activation of the GABAergic system may be of great importance for endogenous ischemic neuroprotection in the brain, whereas other organs also able to induce ischemia tolerance are devoid of this receptor system. Therefore, multiple, partly organ-specific mechanisms may significantly contribute to the acquisition of ischemia resistance.
The kinetics of [3H]muscimol binding in the ischemia-resistant CA1 subfield with a transient increase between 8 and 48 hours after 2.5 minutes of ischemia (Figures 4 and 5) suggest that postischemic upregulation of the GABAergic system in CA1 neurons does not depend on de novo synthesis of receptor proteins, since 528 or 6 hours29 after preconditioning, respectively, protein synthesis in CA1 is still virtually inhibited. Whether affinity of [3H]muscimol binding sites is increased, receptor internalization by endocytosis is inhibited,30 or as yet unknown mechanisms constitute the molecular basis of the observed upregulation of the inhibitory GABAergic system remains to be clarified in future studies. Comparing the kinetics of [3H]muscimol binding and the time course of brain protection does not fit very well at first sight: at 96 hours after a tolerance-inducing 2.5-minute period of ischemia, the time point when the second ischemic insult is superimposed in our model,10,11 enhancement of [3H]muscimol binding is still present yet is no longer significant. Several other investigations also describe protection against ischemic damage by preconditioning for at least 96 hours9 or 7 days.31 When we examine the ratio between ligand binding to excitatory and inhibitory receptors in CA1 after a preconditioning stimulus of 2.5-minute ischemia, however, a significant shift toward binding to inhibitory receptors persists up to 96 hours (Figure 6). Moreover, this shift is already present at 30 minutes after reperfusion, which may have an impact on the initiation of molecular mechanisms that confer neuroprotection.
One other study investigating postischemic [3H]muscimol binding in the gerbil hippocampus after ischemic preconditioning demonstrated no significant changes in ligand binding to GABAA receptors in either hippocampal CA1 and CA3 subfields at 7 days after reperfusion.32 Earlier time points were not analyzed. Although it cannot be excluded that this discrepancy is due to minor variations in the duration of the preconditioning ischemic period (2 versus 2.5 minutes), increased [3H]muscimol binding between 8 and 48 hours after reperfusion would have been missed by these authors.
Despite severe neuronal loss in CA1 after global ischemia of 5 minutes’ duration at 96 hours (Table), [3H]muscimol binding was not significantly reduced in CA1 at any time point investigated (Figures 4 and 5). This surprising phenomenon was also observed by other groups analyzing hippocampal agonist binding to GABAA receptors after global ischemia up to 733,34 or 27 days.35 One possible explanation for this persistence of nearly normal levels of [3H]muscimol binding in postischemic CA1 is an extremely delayed degradation of GABAA receptor binding sites. Alternatively, [3H]muscimol may bind to ischemia-resistant GABAergic interneurons36 or to astrocytes, which also possess GABAA receptors37 and proliferate after the ischemic insult.38 However, labeling of GABAA receptors by other ligands, eg, t-[35S]butylbicyclo-phosphothionate,39,40 [3H]SR-95531,41 or benzodiazepine antagonists42 led to a postischemic decrease in association with cell death.
As anticipated, binding to excitatory NMDA and AMPA receptors after 5 minutes of global ischemia decreased significantly in the vulnerable CA1 subfield in association with neuronal degeneration (Figures 2 and 3). Our present study demonstrates, however, that [3H]MK-801 and [3H]AMPA binding were also transiently reduced in relatively ischemia-resistant CA3 and DG granule neurons after both 5 and 2.5 minutes of global ischemia (Figures 2 and 3). These findings indicate that global ischemia also induces prolonged changes in the abundance of excitatory neurotransmitter receptors in hippocampal regions that do not undergo neuronal degeneration.
Surprisingly, [3H]AMPA binding values in CA1 neurons transiently decreased 24 hours after a preconditioning ischemic period of 2.5 minutes’ duration. There is experimental evidence suggesting that the high-affinity binding site of the AMPA receptor—labeled with the protocol used in the present study—becomes converted to a low-affinity binding site after insertion into the plasma membrane.14,43–45 Therefore, the transient increase of [3H]AMPA binding most likely reflects an intracellular accumulation of AMPA receptors. There are 2 possible explanations for this phenomenon: the postischemic synthesis rate for AMPA receptors is increased, and/or receptor trafficking is altered. The former possibility seems to be relatively unlikely: immunohistochemically, protein expression of AMPA receptor subunits GluR1 and GluR2 in CA1 is not increased.11 Alsbo and colleagues46 demonstrated that GluR3 expression is unaltered after a preconditioning ischemic period in the rat CA1 subfield. The remaining GluR4 subunit, however, is only expressed at low levels in CA147 and is unlikely to contribute to the marked increase in [3H]AMPA ligand binding, as observed in the present study. More attractive is the latter possibility: AMPA receptors are continuously removed from the postsynaptic plasma membrane by endocytosis, followed by reinsertion or degradation.48 Thus, elevated [3H]AMPA ligand labeling due to intracellular accumulation of AMPA receptors after preconditioning would reflect disturbances in the balance between endocytosis, reinsertion, and degradation.
In conclusion, global ischemia of both 5 and 2.5 minutes’ duration causes bidirectional changes of ligand binding to excitatory versus inhibitory receptors, respectively, in the gerbil hippocampus. A reduction of [3H]MK-801 and [3H]AMPA binding to excitatory NMDA and AMPA receptors in relatively ischemia-resistant CA3 and DG granule neurons without neuronal degeneration was observed. This may imply that despite maintained structural integrity, marked postischemic synaptic reorganization processes occur on the subcellular level. More importantly, survival of CA1 neurons after a short ischemic period used for tolerance induction is associated with a transient increase of [3H]muscimol binding to GABAA receptors in hippocampal subfields CA1, CA3, and DG, whereas an ischemic period of 5 minutes’ duration and consecutive DND of hippocampal CA1 principal neurons fail to enhance [3H]muscimol binding in these regions. Thus, our data suggest that a relative shift between inhibitory and excitatory/excitotoxic hippocampal neurotransmission plays a pivotal role in endogenous postischemic neuroprotection of vulnerable neuronal subpopulations.
|
Acknowledgments |
|---|
This work was supported by a grant of the Forschungs-Foerderungsprogramm of the Medical Faculty of the University of Heidelberg (F203415). The authors gratefully acknowledge the excellent technical assistance of Stephan Hennes and Andreas Nussbeck.
Received June 29, 2001; revision received January 24, 2002; accepted February 19, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982; 239: 57–69.[CrossRef][Medline] [Order article via Infotrieve]
2. Lee J-M, Zipfel GJ, Choi DW. The changing landscape of ischaemic brain injury mechanisms. Nature. 1999; 399 (suppl): A7–A14.[Medline] [Order article via Infotrieve]
3. Dawson VL, Dawson TM. Neuronal ischaemic preconditioning. Trends Pharmacol Sci. 2000; 21: 423–424.[CrossRef][Medline] [Order article via Infotrieve]
4. Nellgard B, Wieloch T. Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J Cereb Blood Flow Metab. 1992; 12: 2–11.[Medline] [Order article via Infotrieve]
5. Kato H, Liu Y, Araki T, Kogure K. MK-801, but not anisomycin, inhibits the induction of tolerance to ischemia in the gerbil hippocampus. Neurosci Lett. 1992; 139: 118–121.[CrossRef][Medline] [Order article via Infotrieve]
6. Bond A, Lodge D, Hicks CA, Ward MA, O’Neill MJ. NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus. Eur J Pharmacol. 1999; 380: 91–99.[CrossRef][Medline] [Order article via Infotrieve]
7.
Schwartz-Bloom RD, Sah R. -Aminobutyric acidA neurotransmission and cerebral ischemia. J Neurochem. 2001; 77: 353–371.[CrossRef][Medline]
[Order article via Infotrieve]
8. Nowak TS Jr, Kiessling M. Reprogramming of gene expression.In: Walz W, ed. Cerebral Ischemia: Molecular and Cellular Physiology. Totowa, NJ: Humana Press; 1999: 145–215.
9. Kirino T, Tsujita Y, Tamura A. Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab. 1991; 11: 299–307.[Medline] [Order article via Infotrieve]
10. Sommer C, Gass P, Kiessling M. Selective c-JUN expression in CA1 neurons of the gerbil hippocampus during and after acquisition of an ischemia-tolerant state. Brain Pathol. 1995; 5: 135–144.[Medline] [Order article via Infotrieve]
11.
Sommer C, Kiessling M. Ischemia and ischemia tolerance induction differentially regulate protein expression of GluR1, GluR2, and AMPA receptor binding protein in the gerbil hippocampus: GluR2 (GluR-B) reduction does not predict neuronal death. Stroke. 2002; 33: 1093–1100.
12. Araki T, Kato H, Kogure K, Kanai Y. Long-term changes in gerbil brain neurotransmitter receptors following transient cerebral ischemia. Br J Pharmacol. 1992; 107: 437–442.[Medline] [Order article via Infotrieve]
13. Monaghan DT, Cotman CW. Distribution ofN-methyl-D-aspartate-sensitive L-[3H]glutamate-binding sites in rat brain. J Neurosci. 1985; 5: 2909–2919.[Abstract]
14.
Standley S, Tocco G, Tourigny M-F, Massicotte F, Thompson RF, Baudry M. Developmental changes in -amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor properties and expression in the rat hippocampal formation. Neuroscience. 1995; 67: 881–892.[CrossRef][Medline]
[Order article via Infotrieve]
15. Palacios JM, Wamsley JK, Kuhar MJ. High affinity GABA receptors: autoradiographic localization. Brain Res. 1981; 222: 285–307.[CrossRef][Medline] [Order article via Infotrieve]
16. Zilles K, Wu J, Crusio WE, Schwegler H. Water maze and radial maze learning and the density of binding sites of glutamate, GABA, and serotonin receptors in the hippocampus of inbred mouse strains. Hippocampus. 2000; 10: 213–225.[CrossRef][Medline] [Order article via Infotrieve]
17. Titulaer MN, Kamphuis W, Pool CW, van Heerikhuize JJ, Lopes Da Silva FH. Kindling induces time-dependent and regional specific changes in the [3H]muscimol binding in the rat hippocampus: a quantitative autoradiographic study. Neuroscience. 1994; 59: 817–826.[CrossRef][Medline] [Order article via Infotrieve]
18.
Sternau LL, Lust WD, Ricci AJ, Ratcheson R. Role for -aminobutyric acid in selective vulnerability in gerbils. Stroke. 1989; 20: 281–287.
19. Hall ED, Andrus PK, Fleck TJ, Oostveen JA, Carter DB, Jacobsen EJ. Neuroprotective properties of the benzodiazepine receptor, partial agonist PNU-101017 in the gerbil forebrain ischemia model. J Cereb Blood Flow Metab. 1997; 17: 875–883.[CrossRef][Medline] [Order article via Infotrieve]
20. Hall ED, Fleck TJ, Oostveen JA. Comparative neuroprotective properties of the benzodiazepine receptor full agonist diazepam and partial agonist PNU-101017 in the gerbil forebrain ischemia model. Brain Res. 1998; 798: 325–329.[CrossRef][Medline] [Order article via Infotrieve]
21.
Inglefield JR, Wilson CA, Schwartz-Bloom RD. Effect of transient cerebral ischemia on -aminobutyric acidA receptor 1-subunit-immunoreactive interneurons in the gerbil CA1 hippocampus. Hippocampus. 1997; 7: 551–523.
22. Schwartz-Bloom RD, McDonough KJ, Chase PD, Chadwick LE, Inglefield JR, Levin ED. Long-term protection by benzodiazepine full vs partial agonists following transient cerebral ischemia in the gerbil. J Cereb Blood Flow Metab. 1998; 18: 548–558.[CrossRef][Medline] [Order article via Infotrieve]
23. Dowden J, Reid C, Dooley P, Corbett D. Diazepam-induced neuroprotection: dissociating the effects of hypothermia following global ischemia. Brain Res. 1999; 829: 1–6.[CrossRef][Medline] [Order article via Infotrieve]
24. Schwartz-Bloom RD, Miller KA, Evenson DA, Crain BJ, Nadler JV. Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study. Neuroscience. 2000; 98: 471–483.[CrossRef][Medline] [Order article via Infotrieve]
25. Inglefield JR, Perry JM, Schwartz RD. Post-ischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. Hippocampus. 1995; 5: 460–468.[CrossRef][Medline] [Order article via Infotrieve]
26. Phillis JW. CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil. Gen Pharmacol. 1995; 26: 1061–1064.[Medline] [Order article via Infotrieve]
27.
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischaemia: a delay of lethal cell injury in ischaemic myocardium. Circulation. 1986; 74: 1124–1136.
28. Araki T, Kato H, Inoue T, Kogure K. Regional impairment of protein synthesis following brief cerebral ischemia in the gerbil. Acta Neuropathol (Berl). 1990; 79: 501–505.[CrossRef][Medline] [Order article via Infotrieve]
29. Nakagomi T, Kirinio T, Kanemitsu H, Tsujita Y, Tamura A. Early recovery of protein synthesis following ischemia in hippocampal neurons with induced tolerance in the gerbil. Acta Neuropathol (Berl). 1993; 86: 10–15.[CrossRef][Medline] [Order article via Infotrieve]
30.
Kittler JT, Delmas P, Jovanovic JN, Brown DA, Smart TG, Moss SJ. Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J Neurosci. 2000; 20: 7972–7977.
31. Kato H, Liu Y, Araki T, Kogure K. Temporal profile of effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Res. 1991; 553: 238–242.[CrossRef][Medline] [Order article via Infotrieve]
32. Kato H, Araki T, Kogure K. Preserved neurotransmitter receptor binding following ischemia in the preconditioned gerbil brain. Brain Res Bull. 1992; 29: 395–400.[CrossRef][Medline] [Order article via Infotrieve]
33. Araki T, Kanai Y, Murakami F, Kato H, Kogure K. Postischemic changes in the binding of excitatory and inhibitory neurotransmitters in the gerbil brain. Pharmacol Biochem Behav. 1993; 45: 945–949.[CrossRef][Medline] [Order article via Infotrieve]
34. Murakami F, Araki T, Kanai Y, Kato H, Kogure K. Effect of vinconate against alterations in [3H]naloxone, [3H]MK-801 and [3H]muscimol bindings after transient cerebral ischemia in gerbils. Arch Int Pharmacodyn Ther. 1993; 325: 21–34.[Medline] [Order article via Infotrieve]
35. Onodera H, Sato G, Kogure K. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography. J Cereb Blood Flow Metab. 1987; 7: 82–88.[Medline] [Order article via Infotrieve]
36. Johansen FF, Jørgensen MB, Diemer NH. Resistance of hippocampal CA-1 interneurons to 20 min of transient cerebral ischemia in the rat. Acta Neuropathol (Berl). 1983; 61: 135–140.[CrossRef][Medline] [Order article via Infotrieve]
37. Fraser DD, Medrick-Donnon LA, MacVicar BA. Astrocytic GABA receptors. Glia. 1994; 11: 83–93.[CrossRef][Medline] [Order article via Infotrieve]
38. Kitagawa K, Matsumoto M, Ohtsuki T, Kuwabara K, Mabuchi T, Yagita Y, Hori M, Yanagihara T. Extended neuronal protection induced after sublethal ischemia adjacent to the area with delayed neuronal death. Neuroscience. 2000; 96: 141–146.[CrossRef][Medline] [Order article via Infotrieve]
39. Mileson BE, Ehrmann ML, Schwartz RD. Alterations in the gamma-aminobutyric acid-gated chloride channel following transient forebrain ischemia in the gerbil. J Neurochem. 1992; 58: 600–607.[CrossRef][Medline] [Order article via Infotrieve]
40. Li H, Siegel RE, Schwartz RD. Rapid decline of GABAA receptor mRNA expression in hippocampus following transient cerebral ischemia in the gerbil. Hippocampus. 1993; 3: 527–538.[CrossRef][Medline] [Order article via Infotrieve]
41. Alicke B, Schwartz-Bloom RD. Rapid down-regulation of GABAA receptors in the gerbil hippocampus following transient cerebral ischemia. J Neurochem. 1995; 65: 2808–2811.[Medline] [Order article via Infotrieve]
42. Johansen FF, Christensen T, Jensen MS, Valente E, Jensen CV, Nathan T, Lambert JD, Diemer NH. Inhibition in postischemic rat hippocampus: GABA receptors, GABA release, and inhibitory postsynaptic potentials. Exp Brain Res. 1991; 84: 529–537.[Medline] [Order article via Infotrieve]
43. Honore T, Drejer J. Chaotropic ions affect the conformation of quisqualate receptors in rat cortical membranes. J Neurochem. 1988; 51: 457–461.[CrossRef][Medline] [Order article via Infotrieve]
44. Hall RA, Kessler M, Lynch G. Evidence that high- and low-affinity DL-alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) binding sites reflect membrane-dependent states of a single receptor. J Neurochem. 1992; 59: 1997–2004.[CrossRef][Medline] [Order article via Infotrieve]
45. Dev KK, Henley JM. The regulation of AMPA receptor-binding sites. Mol Neurobiol. 1998; 17: 33–58.[Medline] [Order article via Infotrieve]
46. Alsbo CW, Wrang ML, Johansen FF, Diemer NH. Quantitative PCR analysis of AMPA receptor composition in two paradigms of global ischemia. Neuroreport. 2000; 11: 311–315.[Medline] [Order article via Infotrieve]
47. Martin LJ, Blackstone CD, Levey AI, Huganir RL, Price DL. AMPA glutamate receptor subunits are differentially distributed in rat brain. Neuroscience. 1993; 53: 327–358.[CrossRef][Medline] [Order article via Infotrieve]
48. Ehlers MD. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron. 2000; 28: 511–525.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Yenari, K. Kitagawa, P. Lyden, and M. Perez-Pinzon Metabolic Downregulation: A Key to Successful Neuroprotection? Stroke, October 1, 2008; 39(10): 2910 - 2917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Muller, K. M. Hanumanthiah, K. Diederich, S. Schwab, W.-R. Schabitz, and C. Sommer Brain-Derived Neurotrophic Factor But Not Forced Arm Use Improves Long-Term Outcome After Photothrombotic Stroke and Transiently Upregulates Binding Densities of Excitatory Glutamate Receptors in the Rat Brain Stroke, March 1, 2008; 39(3): 1012 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. Obrenovitch Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia Physiol Rev, January 1, 2008; 88(1): 211 - 247. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||