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Michael V Johnston - One of the best experts on this subject based on the ideXlab platform.
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Perinatal Hypoxic-Ischemic Brain Injury Enhances
2016Co-Authors: Quisqualic Acid-stimulated, Faye S Silverstein, Chukuang K Chen, Stephen K Fisher, Daniel Statman, Phosphoinositide Turnover, Michael V JohnstonAbstract:Abstract: In an experimental model of perinatal hypoxic-ischemic brain injury, we examined Quisqualic Acid (Quis)-stimulated phosphoinositide (PPI) turnover in hippo-campus and striatum. To produce a unilateral forebrain lesion in 7-day-old rat pups, the right carotid artery was ligated and animals were then exposed to moderate hypoxia (8 % oxygen) for 2.5 h. Pups were killed 24 h later and Quis-stimulated PPI turnover was assayed in tissue slices obtained from hippocampus and striatum, target regions for hypoxic-ischemic injury. The glutamate agonist Quis ( 1 0-4 M) preferentially stimulated PPI hydrolysis in injured brain. In hippocampal slices of tissue derived from the right cerebral hemisphere, the addition of Quis stimulated accu-mulation of inositol phosphates by more than ninefold (1,053 k 237 % of basal, mean f SEM, n = 9). In contrast, the addition of Quis stimulated accumulation of inositol phosphates by about fivefold in the contralateral hemi-sphere (588 f 134%) and by about sixfold in controls (631 f 177%, p < 0.005, comparison of ischemic tissue with control). In striatal tissue, the corresponding values were 801 f 157%, 474 f 8996, and 506 k 1 15 % (p < 0.05). In contrast, stimulation of PPI turnover elicited by the cho-linergic agonist carbamoylcholine, ( or lo- ' M) was unaffected by hypoxia-ischemia. The results suggest that prior exposure to hypoxia-ischemia enhances coupling of excitatory amino Acid receptors to phospholipase C activ-ity. This activation may contribute to the pathogenesis of irreversible brain injury and/or to mechanisms of recovery. Key Words: Quisqualic Acid-Inositol phospholipids-Hippocampus-Striatum-Carbamoylcholine-Perinata
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n methyl d aspartate mediated injury enhances Quisqualic Acid stimulated phosphoinositide turnover in perinatal rats
Journal of Neurochemistry, 1992Co-Authors: Chukuang K Chen, Faye S Silverstein, Michael V JohnstonAbstract:Previous work in our laboratory demonstrated that ischemic-hypoxic brain injury in postnatal day 7 rats causes a substantial increase in phosphoinositide (PPI) turnover stimulated by the glutamate analogue Quisqualic Acid (QUIS) in the hippocampus and striatum. To examine this phenomenon in more detail, we performed similar experiments after producing injury by unilateral intracerebral injections of the glutamate analogue N-methyl-D-aspartate (NMDA). The 7-day-old rodent brain is hypersensitive to NMDA neurotoxicity and NMDA injection causes histopathology that closely resembles that produced by ischemia-hypoxia. NMDA, 17 nmol in 0.5 microliter, was injected into the right posterior striatum of 7-day-old rat pups and they were killed 3 days later. Hippocampal or striatal tissue slices were prepared from ipsilateral and contralateral hemispheres from vehicle-injected control and from noninjected control rat pups. Slices were then incubated with myo-[3H]inositol plus glutamate agonists or antagonists in the presence of lithium ions and [3H]inositol monophosphate ([3H]IP1) accumulation was measured. The glutamate agonists, QUIS, L-glutamic Acid, and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, stimulated greater [3H]IP1 release in tissue ipsilateral to the NMDA injection compared with that in the contralateral side and in control pups. The glutamate antagonists, D,L-2-amino-7-phosphonoheptanoic Acid, 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphoric Acid, kynurenic Acid, and 6,7-dinitroquinoxaline-2,3-dione did not inhibit QUIS-stimulated [3H]IP1 release. The enhanced PPI turnover in the lesioned tissue was specific to glutamate receptors because carbachol (CARB) failed to elicit preferential enhanced stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Rodney L. Johnson - One of the best experts on this subject based on the ideXlab platform.
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cyclobutane Quisqualic Acid analogues as selective mglur5a metabotropic glutamic Acid receptor ligands
Journal of Medicinal Chemistry, 1999Co-Authors: Louis Littman, Michael B Robinson, James F. Koerner, Robert J Roon, Shankar Venkatraman, Christopher J Tokar, Rodney L. JohnsonAbstract:The conformationally constrained cyclobutane analogues of Quisqualic Acid (Z)- and (E)-1-amino-3-[2‘-(3‘,5‘-dioxo-1‘,2‘,4‘-oxadiazolidinyl)]cyclobutane-1-carboxylic Acid, compounds 2 and 3, respectively, were synthesized. Both 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus with EC50 values of 18 ± 6 and 53 ± 19 μM, respectively. Neither analogue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a receptors. Compounds 2 and 3 stimulated PI hydrolysis in cells expressing mGluR5a but not in those cells expressing mGluR1a. The EC50 value for 2 was 11 ± 4 μM, while that for 3 was 49 ± 25 μM. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. In addition, neither compound blocked [3H]glutamic Acid uptake into synaptosomal membranes, and neither compound was able to produce the QUIS effect as does Quisqualic Acid. This pharmacological profile indicat...
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Effects of Quisqualic Acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus
Neuropharmacology, 1995Co-Authors: Louis Littman, L.a. Chase, M. Renzi, A.b. Garlin, James F. Koerner, Rodney L. Johnson, Michael B RobinsonAbstract:l-Glutamic Acid (L-Glu) and l-aspartic Acid (L-Asp) activate several receptor subtypes, including metabotropic Glu receptors coupled to phosphoinositide (PI) hydrolysis. Quisqualic Acid (Quis) is the most potent agonist of these receptors. There is evidence that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the Quis effect. The purpose of the current studies was to use Quis analogs and the recently identified metabotropic receptor antagonist, (+)-α-methyl-4-carboxy-phenylglycine((+)-MCPG), to define the structural properties required for interaction with the metabotropic receptors coupled to PI hydrolysis and to determine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or presence of the metabotropic receptor-specific agonist 1SR,3RS-1-amino-1,3-cyclopentanedicarboxylic Acid (1SR,3RS-ACPD) in neonatal rat hippocampus. Some of the compounds that induce the Quis effect also stimulate PI hydrolysis, including Quis itself and 9 (homoQuisqualic Acid). Not all of the Quis analogs that stimulate PI hydrolysis, however, induce the Quis effect, including 7A (EC50 = 750 ± 150 μM) and (RS)-4-bromohomoibotenic Acid (BrHI) (EC50 = 130 ± 40 μM). Although (+)-MCPG blocked PI hydrolysis stimulated by Quis (IC50 = 370 ± 70 μM), it had no effect on the induction of the Quis effect. Other Quis analogs did not stimulate PI hydrolysis but rather blocked the effects of 1SR,3RS-ACPD. The IC50 values were 240 ± 70 μM for 2, 250 ± 90 μM for 3, and 640 ± 200 μM for 4. Data for inhibition by 2 and 3 were consistent with non-competitive mechanisms of action. These studies provide new information about the structural features of Quis required for interaction with metabotropic receptors coupled to PI hydrolysis and provide evidence that the Quis effect is not mediated by (+)-MCPG sensitive subtypes of these receptors.
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synthesis of oxadiazolidinedione derivatives as Quisqualic Acid analogues and their evaluation at a quisqualate sensitized site in the rat hippocampus
Journal of Medicinal Chemistry, 1994Co-Authors: Shankar Venkatraman, James F. Koerner, Marvin K Schulte, Robert J Roon, Rodney L. JohnsonAbstract:The ability of Quisqualic Acid (1) to sensitize neurons to depolarization by omega-phosphono alpha-amino Acid analogues of excitatory amino Acids is a highly specific phenomenon and is termed the QUIS effect. In an attempt to elucidate the structure-activity relationships for this sensitization, analogues 2-6 of Quisqualic Acid have been synthesized. Compounds 4, 5, and 6 showed no quisqualate sensitization with respect to L-2-amino-6-phosphonohexanoic Acid (L-AP6), while compounds 2 and 3 were 1/10 and 1/1000, respectively, as active as Quisqualic Acid in sensitizing neurons toward L-AP6.
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Quisqualic Acid analogues synthesis of β heterocyclic 2 aminopropanoic Acid derivatives and their activity at a novel quisqualate sensitized site
Journal of Medicinal Chemistry, 1992Co-Authors: Nalin L Subasinghe, James F. Koerner, Marvin K Schulte, Robert J Roon, Rodney L. JohnsonAbstract:Hippocampal CA1 pyramidal cell neurons are sensitized over 30-fold to depolarization by L-2-amino-4-phosphonobutanoic Acid (L-AP4) following exposure to L-Quisqualic Acid. This phenomenon has been termed the QUIS effect. In the present study several novel L-Quisqualic Acid analogues have been synthesized and tested for their interaction with the different components of the QUIS-effect system. Replacement of the oxadiazolidinedione ring of L-Quisqualic Acid with several other types of heterocyclic rings yielded the following Quisqualic Acid analogues: maleimide 2, N-methylmaleimide 3, N-(carboxymethyl)maleimide 4, succinimides 5A and 5B, and imidazolidinedione 6. None of these analogues were able to mimic the effects of L-Quisqualic Acid and sensitize hippocampal CA1 neurons to depolarization by L-AP4. Also, unlike L-serine O-sulfate, L-homocysteinesulfinic Acid, or L-alpha-aminoadipic Acid, none of the analogues were able to preblock or reverse the QUIS effect. However, when the IC50 values for inhibition of the CA1 synaptic field potential of analogues 2-6 were determined both before and after hippocampal slices were exposed to L-Quisqualic Acid, the IC50 values of analogues 3 and 4 were found to decrease more than 7-fold. Thus, these two compounds behave like L-AP4 rather than L-Quisqualic Acid in this system in that they exhibit increased potencies in slices that have been pretreated with L-Quisqualic Acid even though they cannot themselves induce this sensitization. Compounds 3 and 4, therefore, represent the first non-phosphorus-containing compounds to which hippocampal neurons become sensitized following exposure to L-Quisqualic Acid. No change in the IC50 values was observed for 5A or 5B. Analogues 2 and 6, on the other hand, displayed a high potency for inhibition of the evoked field potential even prior to treatment of the slices with L-Quisqualic Acid.
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structure function relationships for analogues ofl 2 amino 4 phosphonobutanoic Acid on the Quisqualic Acid sensitive ap4 receptor of the rat hippocampus
Brain Research, 1992Co-Authors: Marvin K Schulte, James F. Koerner, Edward R Whittemore, Rodney L. JohnsonAbstract:Abstract Hippocampal CA1 pyramidal cell neurons are sensitized to depolarization by l -2-amino-4-phosphonobutanoic Acid ( l -AP4) following exposure to l -Quisqualic Acid (QUIS). We have examined the interaction of 43 structural analogues of l -AP4 with both the ‘induction’ site and the QUIS-sensitive AP4 site in rat hippocampus. The synthesis ofcis- andtrans-4-phosphonoxyl- l -proline, 3-(RS)-amino-5-phosphonopentanoic Acid and 2(RS)-amino-5-phenyl-4(RS)-phosphonopentanoic Acid (γ-benzyl AP4) are described. None of the test compounds interact with the induction site; thus l -QUIS remains the only compound known to induce this effect. However, one compound ( l -2-amino-3-(5-tetrazolyl) -propanoic Acid ( l -aspartate tetrazole) ‘pre-blocked’ and reversed the effects of QUIS. In addition, the potency of 16 analogues increased more than 4-fold following exposure of slices to l -QUIS. Among these, l -AP4, l -AP5, 2-amino-4-(methylphosphino) butanoic Acid (AMPB), andE-1(RS)-amino-3(RS)-phosphonocyclopentanecar☐ylic Acid (E-cyclopentyl AP4) diplayed IC50 values of less than 0.100mM after QUIS. The results presented here suggest that the QUIS-sensitive AP4 site requires a spatial configuration of functional groups similar to that present inE-cyclopentyl AP4. The presence of a primary amino group and a phosphorus-containing group (either monoanionic or dianionic) appear to be required, however, a car☐yl group is not essential for interaction. The pharmacology of the QUIS-sensitive AP4 site suggest that it is distinct from other known binding sites for l -AP4 in the central nervous system (CNS).
Richard J Beninger - One of the best experts on this subject based on the ideXlab platform.
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mnemonic deficits in the double y maze are related to the effects of nucleus basalis injections of ibotenic and Quisqualic Acid on choline acetyltransferase in the rat amygdala
Brain Research Bulletin, 1994Co-Authors: Richard J Beninger, Khem Jhamandas, Sylvia Kuhnemann, Janet L Ingles, R J BoegmanAbstract:Many researchers have reported that the magnitude of decrease in cortical choline acetyltransferase (ChAT) following excitotoxic lesions of the nucleus basalis magnocellularis (nbm) is unrelated to the degree of cognitive impairment. Recently, an explanation has been offered for this lack of correlation: different excitotoxins, when injected into the nbm, differentially affected cholinergic projections to the cortex and amygdala, and those excitotoxins previously reported to produce the greatest mnemonic deficits produced the largest decreases in amygdaloid ChAT. The present study evaluated the role of amygdalofugal cholinergic projections in memory by comparing the effects of intra-nbm ibotenic and Quisqualic Acid on cortical and amygdaloid ChAT and on mnemonic performance in the double Y-maze. Rats were trained in the double Y-maze until working and reference memory choice accuracy stabilized to a criterion of > or = 78% correct. Rats then were given either bilateral Quisqualic Acid (60 nmol in 0.5 microliter), bilateral ibotenic Acid (50 nmol in 0.5 microliter), or sham (0.9% saline in 0.5 microliter) lesions of the nbm, and again were tested on the maze. Quisqualate produced a selective impairment of working memory, a large (51%) decrease in cortical ChAT and a small (17%) decrease in amygdaloid ChAT; ibotenate, on the other hand, produced a greater impairment of working memory, an impairment of reference memory, a similar (51%) decrease in cortical ChAT, but a greater (30%) decrease in amygdaloid ChAT. These results suggest that the cholinergic projections from the nbm to the cortex and amygdala play an important role in memory. They suggest that excitotoxins producing greater depletions of amygdaloid ChAT produce greater mnemonic deficits.
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excitotoxic lesions of rat basal forebrain differential effects on choline acetyltransferase in the cortex and amygdala
Neuroscience, 1992Co-Authors: R J Boegman, J Cockhill, Khem Jhamandas, Richard J BeningerAbstract:Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory, However, basal forebrain choiinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase levels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either a-amine-3-hydroxy-5-methyl- 4-isoxazole propionic Acid, ibotenic Acid, Quisqualic Acid, quinolinic Acid or N-methyl-u-aspartic Acid and measuring choline acetyltransferase seven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic Acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, Quisqualic Acid and ~-amine-3-hydroxy-5-methyl-4-jsoxazole were more potent neurotoxins to the cortical projection. cc-Amine-3-hydroxy-5-methyl-4-isozazole propionic Acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic Acid or N-methyl-o-aspartic Acid with little selectivity for choline acetyltransferase depletion in the cortex or amygdala. Histological analysis of the injection site revealed that a~tylcholinesterase-positive neurons were destroyed by the excitotoxins in a dose-dependent manner. Excitotoxins (ibotenic Acid, quinolinic Acid, N-methyl-D-aspartic Acid) that produce the greatest impairments in memory were found to produce the greatest depletion of choline acetyltransferase in the amygdala. These results might suggest that cholinergic neurons projecting to the amygdala play an _- important role in memory. Excitotoxic lesions of the magnocellular cbolinergic neurons in the nucleus basalis (nbm) have been used extensively in studies to examine the effects of cholinergic deaffer~ntation in neurochemical and behavioural experiments.6 When infused inta the nbm axon sparing neurotoxic glutamate receptor agonists such as kainic, ibotenic, Quisqualic or quinolinic Acid produce reductions in cortical choline acetyltrans- ferase (ChAT) activity of up to 80%.'.',9,'2 While these reductions are associated with decreases in perform- ance on memory tasks,
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Excitotoxic lesions of rat basal forebrain: Differential effects on choline acetyltransferase in the cortex and amygdala. Neurosci. 51:129–135
1992Co-Authors: R J Boegman, J Cockhill, Khem Jhamandas, Richard J BeningerAbstract:Abstract-Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory, However, basal forebrain choiinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase l vels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either a-amine-3-hydroxy-5-methyl-4-isoxazole propionic Acid, ibotenic Acid, Quisqualic Acid, quinolinic Acid or N-methyl-u-aspartic Acid and measuring choline acetyltransferase ven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic Acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, Quisqualic Acid and ~-amine-3-hydroxy-5-methyl-4-jsoxazole were more potent neurotoxins to the cortical projection. cc-Amine-3-hydroxy-5-methyl-4-isozazole propionic Acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic Acid or N-methyl-o-aspartic Acid with little selectivity for choline acetyltransferase d pletion in the cortex or amygdala. Histological analysis of the injection site revealed that a~tylcholinesterase-positive n uron
R J Boegman - One of the best experts on this subject based on the ideXlab platform.
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mnemonic deficits in the double y maze are related to the effects of nucleus basalis injections of ibotenic and Quisqualic Acid on choline acetyltransferase in the rat amygdala
Brain Research Bulletin, 1994Co-Authors: Richard J Beninger, Khem Jhamandas, Sylvia Kuhnemann, Janet L Ingles, R J BoegmanAbstract:Many researchers have reported that the magnitude of decrease in cortical choline acetyltransferase (ChAT) following excitotoxic lesions of the nucleus basalis magnocellularis (nbm) is unrelated to the degree of cognitive impairment. Recently, an explanation has been offered for this lack of correlation: different excitotoxins, when injected into the nbm, differentially affected cholinergic projections to the cortex and amygdala, and those excitotoxins previously reported to produce the greatest mnemonic deficits produced the largest decreases in amygdaloid ChAT. The present study evaluated the role of amygdalofugal cholinergic projections in memory by comparing the effects of intra-nbm ibotenic and Quisqualic Acid on cortical and amygdaloid ChAT and on mnemonic performance in the double Y-maze. Rats were trained in the double Y-maze until working and reference memory choice accuracy stabilized to a criterion of > or = 78% correct. Rats then were given either bilateral Quisqualic Acid (60 nmol in 0.5 microliter), bilateral ibotenic Acid (50 nmol in 0.5 microliter), or sham (0.9% saline in 0.5 microliter) lesions of the nbm, and again were tested on the maze. Quisqualate produced a selective impairment of working memory, a large (51%) decrease in cortical ChAT and a small (17%) decrease in amygdaloid ChAT; ibotenate, on the other hand, produced a greater impairment of working memory, an impairment of reference memory, a similar (51%) decrease in cortical ChAT, but a greater (30%) decrease in amygdaloid ChAT. These results suggest that the cholinergic projections from the nbm to the cortex and amygdala play an important role in memory. They suggest that excitotoxins producing greater depletions of amygdaloid ChAT produce greater mnemonic deficits.
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excitotoxic lesions of rat basal forebrain differential effects on choline acetyltransferase in the cortex and amygdala
Neuroscience, 1992Co-Authors: R J Boegman, J Cockhill, Khem Jhamandas, Richard J BeningerAbstract:Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory, However, basal forebrain choiinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase levels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either a-amine-3-hydroxy-5-methyl- 4-isoxazole propionic Acid, ibotenic Acid, Quisqualic Acid, quinolinic Acid or N-methyl-u-aspartic Acid and measuring choline acetyltransferase seven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic Acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, Quisqualic Acid and ~-amine-3-hydroxy-5-methyl-4-jsoxazole were more potent neurotoxins to the cortical projection. cc-Amine-3-hydroxy-5-methyl-4-isozazole propionic Acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic Acid or N-methyl-o-aspartic Acid with little selectivity for choline acetyltransferase depletion in the cortex or amygdala. Histological analysis of the injection site revealed that a~tylcholinesterase-positive neurons were destroyed by the excitotoxins in a dose-dependent manner. Excitotoxins (ibotenic Acid, quinolinic Acid, N-methyl-D-aspartic Acid) that produce the greatest impairments in memory were found to produce the greatest depletion of choline acetyltransferase in the amygdala. These results might suggest that cholinergic neurons projecting to the amygdala play an _- important role in memory. Excitotoxic lesions of the magnocellular cbolinergic neurons in the nucleus basalis (nbm) have been used extensively in studies to examine the effects of cholinergic deaffer~ntation in neurochemical and behavioural experiments.6 When infused inta the nbm axon sparing neurotoxic glutamate receptor agonists such as kainic, ibotenic, Quisqualic or quinolinic Acid produce reductions in cortical choline acetyltrans- ferase (ChAT) activity of up to 80%.'.',9,'2 While these reductions are associated with decreases in perform- ance on memory tasks,
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Excitotoxic lesions of rat basal forebrain: Differential effects on choline acetyltransferase in the cortex and amygdala. Neurosci. 51:129–135
1992Co-Authors: R J Boegman, J Cockhill, Khem Jhamandas, Richard J BeningerAbstract:Abstract-Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory, However, basal forebrain choiinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase l vels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either a-amine-3-hydroxy-5-methyl-4-isoxazole propionic Acid, ibotenic Acid, Quisqualic Acid, quinolinic Acid or N-methyl-u-aspartic Acid and measuring choline acetyltransferase ven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic Acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, Quisqualic Acid and ~-amine-3-hydroxy-5-methyl-4-jsoxazole were more potent neurotoxins to the cortical projection. cc-Amine-3-hydroxy-5-methyl-4-isozazole propionic Acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic Acid or N-methyl-o-aspartic Acid with little selectivity for choline acetyltransferase d pletion in the cortex or amygdala. Histological analysis of the injection site revealed that a~tylcholinesterase-positive n uron
James F. Koerner - One of the best experts on this subject based on the ideXlab platform.
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l Quisqualic Acid transport into hippocampal neurons by a cystine sensitive carrier is required for the induction of quisqualate sensitization
Neuroscience, 2001Co-Authors: L.a. Chase, Robert J Roon, L Wellman, Alvin J Beitz, James F. KoernerAbstract:Abstract A brief exposure of hippocampal slices to L -Quisqualic Acid sensitizes CA1 pyramidal neurons 30–250-fold to depolarization by two classes of excitatory amino Acid analogues: (1) those whose depolarizing effects are rapidly terminated following washout, e.g. L -2-amino-4-phosphonobutanoic Acid ( L -AP4) and L -2-amino-6-phosphonohexanoic Acid ( L -AP6) and (2) those whose depolarizing effects persist following washout, e.g. L -aspartate-β-hydroxamate ( L -AβH). This process has been termed quisqualate sensitization. In this study we directly examine the role of amino Acid transport systems in the induction of quisqualate sensitization. We report that L -quisqualate is a low-affinity substrate ( K M =0.54 mM) for a high capacity ( V max =0.9 nmol (mg protein) −1 min −1 ) Na + -dependent transport system(s) and a high-affinity substrate ( K M =0.033 mM) for a low-capacity ( V max =0.051 nmol (mg protein) −1 min −1 ) transporter with properties similar to the cystine/glutamate exchange carrier, System x c − . We present evidence that suggests that System x c − participates in quisqualate sensitization. First, simultaneous application of L -quisqualate and inhibitors of System x c − , but not inhibitors of Na + -dependent glutamate transporters, prevents the subsequent sensitization of hippocampal neurons to phosphonates or L -AβH. Second, L -Quisqualic Acid only sensitizes hippocampal neurons to other substrates of System x c − , including cystine. Third, immunocytochemical analysis of L -quisqualate uptake demonstrates that only inhibitors of System x c − inhibit the highly concentrative uptake of L -quisqualate into a widely dispersed group of GABAergic hippocampal interneurons. We conclude that quisqualate sensitization is a direct consequence of the unique interaction of various excitatory amino Acids, namely L -quisqualate, cystine, and phosphonates, with the exchange carrier, System x c − . Therefore, the results of this study have important implications for the mechanism by which L -quisqualate, and other substrates of this transporter which are also excitatory amino Acid agonists (such as glutamate and β- N -oxalyl- L -α,β-diaminopropionic Acid, β- L -ODAP) may trigger neurotoxicity.
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cyclobutane Quisqualic Acid analogues as selective mglur5a metabotropic glutamic Acid receptor ligands
Journal of Medicinal Chemistry, 1999Co-Authors: Louis Littman, Michael B Robinson, James F. Koerner, Robert J Roon, Shankar Venkatraman, Christopher J Tokar, Rodney L. JohnsonAbstract:The conformationally constrained cyclobutane analogues of Quisqualic Acid (Z)- and (E)-1-amino-3-[2‘-(3‘,5‘-dioxo-1‘,2‘,4‘-oxadiazolidinyl)]cyclobutane-1-carboxylic Acid, compounds 2 and 3, respectively, were synthesized. Both 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus with EC50 values of 18 ± 6 and 53 ± 19 μM, respectively. Neither analogue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a receptors. Compounds 2 and 3 stimulated PI hydrolysis in cells expressing mGluR5a but not in those cells expressing mGluR1a. The EC50 value for 2 was 11 ± 4 μM, while that for 3 was 49 ± 25 μM. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. In addition, neither compound blocked [3H]glutamic Acid uptake into synaptosomal membranes, and neither compound was able to produce the QUIS effect as does Quisqualic Acid. This pharmacological profile indicat...
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Effects of Quisqualic Acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus
Neuropharmacology, 1995Co-Authors: Louis Littman, L.a. Chase, M. Renzi, A.b. Garlin, James F. Koerner, Rodney L. Johnson, Michael B RobinsonAbstract:l-Glutamic Acid (L-Glu) and l-aspartic Acid (L-Asp) activate several receptor subtypes, including metabotropic Glu receptors coupled to phosphoinositide (PI) hydrolysis. Quisqualic Acid (Quis) is the most potent agonist of these receptors. There is evidence that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the Quis effect. The purpose of the current studies was to use Quis analogs and the recently identified metabotropic receptor antagonist, (+)-α-methyl-4-carboxy-phenylglycine((+)-MCPG), to define the structural properties required for interaction with the metabotropic receptors coupled to PI hydrolysis and to determine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or presence of the metabotropic receptor-specific agonist 1SR,3RS-1-amino-1,3-cyclopentanedicarboxylic Acid (1SR,3RS-ACPD) in neonatal rat hippocampus. Some of the compounds that induce the Quis effect also stimulate PI hydrolysis, including Quis itself and 9 (homoQuisqualic Acid). Not all of the Quis analogs that stimulate PI hydrolysis, however, induce the Quis effect, including 7A (EC50 = 750 ± 150 μM) and (RS)-4-bromohomoibotenic Acid (BrHI) (EC50 = 130 ± 40 μM). Although (+)-MCPG blocked PI hydrolysis stimulated by Quis (IC50 = 370 ± 70 μM), it had no effect on the induction of the Quis effect. Other Quis analogs did not stimulate PI hydrolysis but rather blocked the effects of 1SR,3RS-ACPD. The IC50 values were 240 ± 70 μM for 2, 250 ± 90 μM for 3, and 640 ± 200 μM for 4. Data for inhibition by 2 and 3 were consistent with non-competitive mechanisms of action. These studies provide new information about the structural features of Quis required for interaction with metabotropic receptors coupled to PI hydrolysis and provide evidence that the Quis effect is not mediated by (+)-MCPG sensitive subtypes of these receptors.
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synthesis of oxadiazolidinedione derivatives as Quisqualic Acid analogues and their evaluation at a quisqualate sensitized site in the rat hippocampus
Journal of Medicinal Chemistry, 1994Co-Authors: Shankar Venkatraman, James F. Koerner, Marvin K Schulte, Robert J Roon, Rodney L. JohnsonAbstract:The ability of Quisqualic Acid (1) to sensitize neurons to depolarization by omega-phosphono alpha-amino Acid analogues of excitatory amino Acids is a highly specific phenomenon and is termed the QUIS effect. In an attempt to elucidate the structure-activity relationships for this sensitization, analogues 2-6 of Quisqualic Acid have been synthesized. Compounds 4, 5, and 6 showed no quisqualate sensitization with respect to L-2-amino-6-phosphonohexanoic Acid (L-AP6), while compounds 2 and 3 were 1/10 and 1/1000, respectively, as active as Quisqualic Acid in sensitizing neurons toward L-AP6.
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Quisqualic Acid induced sensitization and the active uptake of l Quisqualic Acid by hippocampal slices
Brain Research, 1993Co-Authors: Marvin K Schulte, Robert J Roon, James F. KoernerAbstract:Hippocampal CA1 pyramidal cell neurons are sensitized to depolarization by L-2-amino-4-phosphonobutanoic Acid (L-AP4) following exposure to L-Quisqualic Acid (QUIS). It has been proposed that induction of this 'QUIS-effect' involves uptake of L-QUIS by hippocampal cells. We have used o-phthaldialdehyde (OPA) derivatization and high performance liquid chromatographic (HPLC) separation of extracts from hippocampal slices which have been exposed to varied concentrations of L-QUIS to investigate L-QUIS uptake into hippocampal slices. We observe uptake rates such that the internal concentration of L-QUIS exceeds the bath concentration within 7 min. The fact that this uptake is concentrative indicates that it is mediated by an active transport system. In addition, uptake of L-QUIS may be linked to the induction of the QUIS-effect. At low concentrations of L-QUIS (< 4 microM), the QUIS-effect is only partially induced within the 4 min incubation time which maximally induces the effect when 16 microM L-QUIS is used. However, repeated 4 min exposure periods of slices to low L-QUIS concentrations will eventually induce the QUIS-effect even when each exposure is separated by extensive washout periods. Hence induction is dependent on both concentration and total exposure time. We also examined the effects of L-alpha-aminoadipic Acid and L-serine-O-sulfate on the rate of L-QUIS uptake. Exposure of slices to these compounds prior to treatment with L-QUIS will block the physiological effects of L-QUIS. We found that these 'pre-blocking' compounds did not decrease the rate of L-QUIS uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
