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ABSTRACT: The hyperactivity of ionotropic glutamate receptors has been implicated in the development of the neuronal cell death seen in many neurodegenerative processes including ischemic stroke, traumatic brain injury, and epilepsy. Thus neuronal protection against glutamate-induced neurotoxicity is considered as an appropriate therapeutic strategy for preventing and treating neurodegenerative diseases. Whilst searching for blockers of glutamate-induced toxicity in mouse cortical cells, we isolated p-terphenyl curtisians A - D from the mushroom Paxillus curtisii. Curtisians protected cortical neurons from glutamate-induced toxicity in a dose-dependent manner. Among the glutamate receptor subtypes, curtisians were found to block NMDA receptor-mediated but not AMPA/kainate-mediated cell death. In addition, we found that curtisians exhibited potent antioxidative activity against iron-mediated oxidative damage which was generated by H2O2 neurotoxocity and lipid peroxidation, but no activity was detected in the superoxide, DPPH and ABTS radical scavenging systems, and in protection of N18-RE-105 cells subjected to glutamate-induced glutathione depletion. This effect was likely due to the iron chelating properties of curtisians. The iron chelation ability of curtisians was then further investigated on DNA single strand breakage (SSB) induced by the addition of iron and H2O2, and curtisians prevented DNA SSB like the iron chelator desferrioxamine. These results suggest that the neuroprotective action of curtisians is dependent on their ability to chelate iron as well as to block the NMDA receptor, and that in this context curtisians may be useful as neuroprotective agents against neurological disorders which result in neuronal cell death.
Planta Medica 07/2003; 69(6):513-7. · 2.15 Impact Factor
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ABSTRACT: Excitatory amino acids are known to induce considerable neurotoxicity in central nervous system. In the present study, the neurotoxicity was induced by application of kainate or AMPA in chick telencephalic neuron, and neuroprotective activity was tested with complestatin that was isolated from streptomyces species. In cultured telencephalic neurons exposed to 500 microM kainate for 2 days, the AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 5 microM) completely blocked kainate-induced neurotoxicity. Also, complestatin (0.5 microM) completely blocked kainate-induced neuronal injury at a concentration lower than that required for prototype AMPA/kainate receptor antagonist DNQX. In addition, complestatin blocked AMPA-induced neurotoxicity when the neurons were pretreated with cyclothiazide, a desensitization blocker of AMPA receptor. Surprisingly, when the onset of the treatment was delayed for 6 hours, complestatin led to a reduction in kainate-induced neuronal injury. While inhibition of protein kinase C (PKC) by staurosporin induced neurotoxicity, that was blocked by complestatin. Activation of PKC by phorbol dibutyrate partially inhibited the kainate-induced neurotoxicity. These results suggest that complestatin may be used as an anti-excitotoxic agent and involved in the PKC activation contributing to inhibition of neurotoxicity.
Neurochemical Research 05/2002; 27(4):337-43. · 2.24 Impact Factor
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ABSTRACT: Excitatory amino acids are known to induce considerable neurotoxicity in central nervous system. In the present study, the neurotoxicity was induced by application of kainate or AMPA in chick telencephalic neuron, and neuroprotective activity was tested with complestatin that was isolated from streptomyces species. In cultured telencephalic neurons exposed to 500 M kainate for 2 days, the AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 5 M) completely blocked kainate-induced neurotoxicity. Also, complestatin (0.5 M) completely blocked kainate-induced neuronal injury at a concentration lower than that required for prototype AMPA/kainate receptor antagonist DNQX. In addition, complestatin blocked AMPA-induced neurotoxicity when the neurons were pretreated with cyclothiazide, a desensitization blocker of AMPA receptor. Surprisingly, when the onset of the treatment was delayed for 6 hours, complestatin led to a reduction in kainate-induced neuronal injury. While inhibition of protein kinase C (PKC) by staurosporin induced neurotoxicity, that was blocked by complestatin. Activation of PKC by phorbol dibutyrate partially inhibited the kainate-induced neurotoxicity. These results suggest that complestatin may be used as an anti-excitotoxic agent and involved in the PKC activation contributing to inhibition of neurotoxicity.
Neurochemical Research 01/2002; 27(4):337-343. · 2.24 Impact Factor
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ABSTRACT: In this study, N-methyl-d-aspartate (NMDA)-receptor antagonists enhanced the head-twitch response induced by 5-hydroxytryptamine (5-HT) in reserpine-treated mice.To minimize the risk of any indirect involvement of NMDA-receptor antagonists (d(-)-2-amino-5-phosphonopentanoic acid (AP-5), l(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP), (+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-imine (MK-801), ketamine, dextrorphan and dextromethorphan) with 5-HT neurones, vesicle stores of monoamines, especially 5-HT, were depleted with reserpine. In addition, the enhancement of 5-HT-induced head-twitch response was inhibited by apomorphine and NMDA as well as ritanserin in reserpine-treated mice.These results support our previous conclusion that NMDA receptors play important roles in the glutamatergic modulation of 5-HTergic function at the postsynaptic 5-HT2 receptors in mice.
Journal of Pharmacy and Pharmacology. 05/2000; 52(6):717 - 722.
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ABSTRACT: These studies were designed to examine the differential effect of nitric oxide (NO) and cGMP on glutamate neurotransmission.
In primary cultures of rat cerebellar granule cells, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulates
the elevation of intracellular calcium concentration ([Ca2+]i), the release of glutamate, the synthesis of NO and an increase of cGMP. Although NO has been shown to stimulate guanylyl
cyclase, it is unclear yet whether NO alters the NMDA-induced glutamate release and [Ca2+]i elevation. We showed that the NO synthase inhibitor, NG-monomethyl-L-arginine (NMMA), partially prevented the NMDA-induced release of glutamate and elevation of [Ca2+]i and completely blocked the elevation of cGMP. These effects of NO on glutamate release and [Ca2+]i elevation were unlikely to be secondary to cGMP as the cGMP analogue, dibutyryl cGMP (dBcGMP), did not suppress the effects
of NMDA. Rather, dBcGMP slightly augmented the NMDA-induced elevation of [Ca2+]i with no change in the basal level of glutamate or [Ca2+]i. The extracellular NO scavenger hydroxocobalamine prevented the NMDA-induced release of glutamate providing indirect evidence
that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining
the NMDA receptor activation in a cGMP-independent manner.
Archives of Pharmacal Research 04/1999; 22(1):48-54. · 1.59 Impact Factor
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ABSTRACT: In the present study, we have investigated the effects of prolonged inhibition of NMDA receptor by infusion of subtoxic dose of MK-801 to examine the modulation of GABAA receptor binding and GABAA receptor subunit mRNA level in rat brain. It has been reported that NMDA-selective glutamate receptor stimulation alters GABAA receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunit. However, we have investigated the effect of NMDA antagonist, MK-801, on GABAA receptor binding characteristics in discrete brain regions by using autoradiographic and in situ hybridization techniques. The GABAA receptor bindings were analyzed by quantitative autoradiography using [3H]muscimol, [3H]flunitrazepam, and [35S]TBPS in rat brain slices. Rats were infused with MK-801 (1 pmol/10 μl per h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 2ML). The levels of [3H]muscimol binding were highly elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, and cerebellum. However, the [3H]flunitrazepam binding and [35S]TBPS binding were increased only in specific regions; the former level was increased in parts of the cortex, thalamus, and hippocampus, while the latter binding sites were only slightly elevated in parts of thalamus. The levels of β2-subunit were elevated in the frontal cortex, thalamus, hippocampus, brainstem, and cerebellar granule layers while the levels of β3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in MK-801-infused rats. The levels of α6- and δ-subunits, which are highly localized in the cerebellum, were increased in the cerebellar granule layer after MK-801 treatment. These results show that the prolonged suppression of NMDA receptor function by MK-801-infusion strongly elevates [3H]muscimol binding throughout the brain, increases regional [3H]flunitrazepam and [35S]TBPS binding, and alters GABAA receptor subunit mRNA levels in different directions. The chronic MK-801 treatment has differential effect on various GABAA receptor subunits, which suggests involvement of differential regulatory mechanisms in interaction of NMDA receptor with the GABA receptors.
Brain Research.
