Rapid desensitization determines the pharmacology of glutamate neurotoxicity

Moudy, Anna M.; Yamada, Kelvin A.; Rothman, Steven M.

doi:10.1016/0028-3908(94)90153-8

Cited by 66 publications

(27 citation statements)

References 35 publications

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“…Moreover, tremendous variation exists among desensitization rates (1.5-l 8 msec) between different hippocampal neurons (Tang and Shi, 1991;Livsey and Vicini, 1993). In contrast, deactivation rates are more rapid and vary least (2-3 msec) between different hippocampal neurons (Colquhoun et al, 1992;Livsey and Vicini, 1993 (Moudy et al, 1992;Bateman et al, 1993;Zorumski et al, 1993 suggests that GYKI 52466 may oppose CYZ's effects by acting at such a postulated modulatory site. Palmer and Lodge (1993) have observed that CYZ reverses the inhibition of AMPA responses by GYKI 53655, but not NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline, a quinoxalinedionecompetitive AMPA antagonist).…”

Section: Physiological Roles Of Desensitizationmentioning

confidence: 99%

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

1993

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A distinctive characteristic of the AMPA subset of glutamate receptor channels is their remarkably rapid desensitization. A family of compounds, the benzothiadiazides, is described here that potently inhibit rapid glutamate receptor desensitization. The structure- activity relationships of these compounds are examined and the actions of cyclothiazide (CYZ), the most potent of these compounds, are described in detail. At the macroscopic level CYZ reduced rapid desensitization, enhancing the steady-state and peak current produced by 1 mM quisqualate with EC50 values of 14 and 12 microM, respectively, and shifted the quisqualate peak current concentration-response relation to the left. The slight outward rectification of the steady- state quisqualate current-voltage relationship was reduced by CYZ. At the microscopic level CYZ caused glutamate to induce long bursts of channel openings, and greatly increased the number of repeated openings. At 10 microM CYZ did not have measurable effects on the fast component of deactivation nor did it have statistically significant effects on the distribution of the faster components of glutamate- induced burst duration. In contrast, 10 microM CYZ increased the amplitude and significantly prolonged the duration of the spontaneous miniature EPSCs. The identification and characterization of this new family of gating modifiers may further facilitate the investigation into the mechanisms underlying rapid glutamate receptor desensitization and the physiological roles that it may serve.

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Section: Physiological Roles Of Desensitizationmentioning

confidence: 99%

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

1993

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“…A number of observations make it attractive to think that there may be a specific modulatory site by which cyclothiazide exerts its effects upon AMPA desensitization and upon antagonists of the AMPA receptor, and evidence is accumulating that suggests that modulation via such a site may have clinically relevant implications (Moudy et al, 1994;Zivkovic et al, 1995). First, cyclothiazide is AMPA receptor selective (Partin et al, 1993), and affects desensitization of flip splice variants more efficaciously and with higher affinity than flop splice variants (Partin et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists

Yamada

Turetsky

1996

British J Pharmacology

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1 Cyclothiazide blocks a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization and potentiates AMPA receptor gated currents. Interactions between cyclothiazide, and the non-competitive antagonist GYK152466 (GYKI) and competitive antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F) quinoxaline (NBQX) were studied at native and recombinant AMPA/kainate receptors using whole-cell recording in order to characterize the modulation by cyclothiazide of these two antagonist sites.

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“…Moudy et al (16) have reported that in cultures of rat hippocampal neurons cyclothiazide dramatically potentiated the neurotoxic action of glutamate even when the experiment was conducted in the presence of a large dose of dizocilpine to exclude the role of NMDA receptors in the neurotoxic action of glutamate. We have confirmed that in cultures of cerebellar granule neurons, 5 to 10 M cyclothiazide applied together with glutamate or AMPA and in the presence of dizocilpine is neurotoxic.…”

Section: Discussionmentioning

confidence: 99%

“…Concerns have been raised, however, regarding the therapeutic use of inhibitors of the rapidly occurring agonist-dependent AMPA receptor desensitization because of their potential neurotoxic liability (16,17). Moudy et al (16) showed that in primary cultures of hippocampal neurons prepared from rat embryos, the increase in duration of AMPA-gated channel function by cyclothiazide or diazoxide resulted in a strong amplification of the Ca 2ϩ transients, leading to excitotoxicity.…”

mentioning

confidence: 99%

“…Moudy et al (16) showed that in primary cultures of hippocampal neurons prepared from rat embryos, the increase in duration of AMPA-gated channel function by cyclothiazide or diazoxide resulted in a strong amplification of the Ca 2ϩ transients, leading to excitotoxicity. Thus, we considered it important to compare in dissociated primary neuronal cultures of neonatal rats the potency and intrinsic activity of cyclothiazide and IDRA-21 on AMPA-mediated Na ϩ and Ca 2ϩ influx with their respective neurotoxic liabilities.…”

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confidence: 99%

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7-Chloro-3-methyl-3,4-dihydro-2 H -1,2,4-benzothiadiazine S , S -dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity

Impagnatiello

Oberto

Longone

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of ␣-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca 2؉ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca 2؉ -dependent f luorescence and intracellular Na ؉ measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester f luorescence indicator. IDRA-21 increases intracellular Na ؉ transient with a threshold (5 M) that is Ϸ10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide. By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca 2؉ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cells for several minutes. Additionally, while dose dependently, 5-25 M cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 M) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist). Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than those required to elicit marginal neurotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

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Rapid desensitization determines the pharmacology of glutamate neurotoxicity

Cited by 66 publications

References 35 publications

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists

7-Chloro-3-methyl-3,4-dihydro-2 H -1,2,4-benzothiadiazine S , S -dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity

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