Kainate excitotoxicity is mediated by AMPA- but not kainate-preferring receptors in embryonic rat hippocampal cultures

Ohno, Kiyoshi; Okada, Masamichi; Tsutsumi, Rie; Kohara, Atsuyuki; Yamaguchi, Tokio

doi:10.1016/s0197-0186(97)00011-9

Cited by 32 publications

(35 citation statements)

References 42 publications

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“…By using the selective non-competitive AMPA receptor antagonist LY 303070, our group has previously demonstrated that the neurotoxic effect of KA in short-term exposures (30 min), in the presence of CTZ, is mediated by the AMPA receptor (Ambrosio et al 2000). The property of blocking AMPA receptor desensitization by CTZ is a powerful tool to unmask AMPA receptor effects, since KA alone was not toxic (during 5-or 15-min exposure, data not shown), and also results in increased neurotoxicity, as previously shown (Cebers et al 1997;Ohno et al 1997;Ferreira et al 1998;Jensen et al 1998b;Ohno et al 1998;Ambrosio et al 2000).…”

Section: Discussionmentioning

confidence: 56%

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Araújo

Ambrósio

Leal

et al. 2003

Journal of Neurochemistry

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In this work, we investigated the role of nitric oxide (NO) in neurotoxicity triggered by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in cultured hippocampal neurons. In the presence of cyclothiazide (CTZ), short-term exposures to kainate (KA; 5 and 15 min, followed by 24-h recovery) decreased cell viability. Both NBQX and D-AP-5 decreased the neurotoxicity caused by KA plus CTZ. Long-term exposures to KA plus CTZ (24 h) resulted in increased toxicity. In short-, but not in long-term exposures, the presence of NO synthase (NOS) inhibitors (L-NAME and 7-NI) decreased the toxicity induced by KA plus CTZ. We also found that KA plus CTZ (15-min exposure) significantly increased cGMP levels. Furthermore, short-term exposures lead to decreased intracellular ATP levels, which was prevented by NBQX, D-AP-5 and NOS inhibitors. Immunoblot analysis revealed that KA induced neuronal NOS (nNOS) proteolysis, gradually lowering the levels of nNOS according to the time of exposure. Calpain, but not caspase-3 inhibitors, prevented this effect. Overall, these results show that NO is involved in the neurotoxicity caused by activation of nondesensitizing AMPA receptors, although to a limited extent, since AMPA receptor activation triggers mechanisms that lead to nNOS proteolysis by calpains, preventing a further contribution of NO to the neurotoxic process.

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Section: Discussionmentioning

confidence: 56%

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Araújo

Ambrósio

Leal

et al. 2003

Journal of Neurochemistry

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“…Previous studies have demonstrated that excitotoxicity induced by kainate stimulation is mediated by AMPA-but not by kainate-preferring receptors in hippocampal neurons and in amacrine-like neurons in culture (Ohno et al, 1997;Ferreira et al, 1998;Ambrósio et al, 2000). Kainate receptors can, however, mediate selective responses (Paternain et al, 1995), especially in the presence of Con A (Savidge et al, 1997;Jensen et al, 1998).…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, the results also indicate that kainate receptor desensitization play an important role in kainate-induced increase in intracellular free Ca 2ϩ . The role of AMPA receptors desensitization on the neuronal viability has been extensively studied recently (Ohno et al, 1997;Ferreira at al., 1998;Ambrósio et al, 2000), but for several years the role of kainate receptors remained elusive. The specific role of kainate receptors as modulators of synaptic transmission has, however already been revealed (Paternain et al, 1995;Jones et al, 1997;Wilding and Huetter, 1997;Malva et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Although some studies show that kainate-induced toxicity is mainly due to the activation of AMPA receptors (Ohno et al, 1997;Ferreira et al, 1998;Ambrósio et al, 2000), other reports also demonstrate the presence of functional kainate receptors (Parternain et al, 1995) and their involvement in excitotoxicity (Sánchez-Gómez and Matute, 1999). Selective agonists and antagonists to AMPA and kainate receptors have been used to unmask the role of kainate receptors (Malva et al, 1995;Savidge et al, 1997;Bleakman et al, 1998).…”

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confidence: 99%

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Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Silva¹,

Malva²,

Ambrósio³

et al. 2001

J of Neuroscience Research

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We investigated the role of kainate (KA) receptor activation and desensitization in inducing the increase in the intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ) in individual cultured rat hippocampal neurons. The rat hippocampal neurons in the cultures were shown to express kainate receptor subunits, KA2 and GluR6/7, either by immunocytochemistry or by immunoblot analysis. The effect of LY303070, an ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor antagonist, on the alterations in the [Ca 2ϩ ] i caused by kainate showed cell-tocell variability. The [Ca 2ϩ ] i increase caused by kainate was mostly mediated by the activation of AMPA receptors because LY303070 inhibited the response to kainate in a high percentage of neurons. The response to kainate was potentiated by concanavalin A (Con A), which inhibits kainate receptor desensitization, in 82.1% of the neurons, and this potentiation was not reversed by LY303070 in about 38% of the neurons. Also, upon stimulation of the cells with 4-methylglutamate (MGA), a selective kainate receptor agonist, in the presence of Con A, it was possible to observe [Ca 2ϩ ] i changes induced by kainate receptor activation, because LY303070 did not inhibit the response in all neurons analyzed. In toxicity studies, cultured rat hippocampal neurons were exposed to the drugs for 30 min, and the cell viability was evaluated at 24 hr using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The selective activation of kainate receptors with MGA, in the presence of Con A, induced a toxic effect, which was not prevented by LY303070, revealing a contribution of a small subpopulation of neurons expressing kainate receptors that independently mediate cytotoxicity. Taken together, these results indicate that cultured hippocampal neurons express not only AMPA receptors, but also kainate receptors, which can modulate the [Ca 2ϩ ] i and toxicity. J. Neurosci. Res. 65:378 -386, 2001.

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“…To create new orally active AMPA receptor antagonists, a hundred thousand compounds have been screened against KA-induced toxicity in rat primary cortical cultures, which is mediated by the AMPA receptor (Ohno et al, 1997). Several active compounds with potentially useful chemical structures were found, and from these, a pyridothiazine derivative was selected as a lead compound.…”

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confidence: 99%

Functional Characterization of YM928, a Novel Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist

Ohno¹,

Tsutsumi²,

Matsumoto³

et al. 2003

J Pharmacol Exp Ther

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The ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is thought to play an important role in the pathogenesis of several neurological disorders as well as normal brain function. The search for AMPA receptor antagonists as potential therapeutics is ongoing. Here, we describe the functional characterization of a novel noncompetitive AMPA receptor antagonist, 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (YM928). This compound inhibited AMPA receptor-mediated toxicity in primary rat hippocampal cultures with an IC 50 of 2 M. Its manner of inhibition was noncompetitive as the agonist concentration was increased. YM928 blocked AMPA-induced intracellular calcium influx with an IC 50 of 3 M and antagonized AMPA-induced inward currents with an IC 50 of 1 M in cultured cells. YM928 displaced neither [ 3 H]AMPA binding nor other existing glutamate receptor-related ligand binding in rat brain membranes. In terms of in vivo activity, YM928 had an anticonvulsant effect in sound-induced seizures in DBA/2 mice 45 min after oral administration at 3 mg/kg. Thus, YM928 has potential as an oral therapeutic drug for various types of neurological disorders.

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Kainate excitotoxicity is mediated by AMPA- but not kainate-preferring receptors in embryonic rat hippocampal cultures

Cited by 32 publications

References 42 publications

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons

Functional Characterization of YM928, a Novel Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist

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Kainate excitotoxicity is mediated by AMPA- but not kainate-preferring receptors in embryonic rat hippocampal cultures

Cited by 32 publications

References 42 publications

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Role of kainate receptor activation and desensitization on the [Ca2+]i changes in cultured rat hippocampal neurons

Functional Characterization of YM928, a Novel Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist

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Role of kainate receptor activation and desensitization on the [Ca²⁺]_i changes in cultured rat hippocampal neurons