Over-additive protective effect of dizocilpine and NBQX against neuronal damage

Lippert, Klaus; Welsch, M.; Krieglstein, Josef

doi:10.1016/0014-2999(94)90193-7

Cited by 46 publications

(13 citation statements)

References 27 publications

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“…The permanent middle cerebral artery occlusion (MCAO) was established by means of microbipolar permanent coagulation in NMRI mice (35-45 g) anesthetized with tribromoethanol, 600 mg͞kg i.p. (25), or in Fischer 344 rats (260-290 g) anesthetized with halothane (26). For determination of the therapeutic time window, ZK200775 was continuously infused i.v.…”

Section: Methodsmentioning

confidence: 99%

ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma

Turski

Huth

Sheardown

et al. 1998

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

151

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Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-aspartate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.

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Section: Methodsmentioning

confidence: 99%

ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma

Turski

Huth

Sheardown

et al. 1998

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

151

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“…There is evidence from animal studies that AMPA and kainate receptor antagonists may also have neuroprotective effects in ischaemic stroke and epilepsy. [15][16][17][18][19][20] Moreover, the proposal of chronic pain being relieved by antagonists of kainate and perhaps also of AMPA receptors receives growing support. 9 10 15 An antagonistic effect of Xe on AMPA receptors was not apparent in a study using an indirect approach at native neurones, but was postulated after currents conducted by AMPA receptor channels in heterologous expression systems had been directly investigated.…”

mentioning

confidence: 99%

Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones

Dinse¹,

Föhr²,

Georgieff³

et al. 2005

British Journal of Anaesthesia

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“…These observations are consistent with the hypothesis that NMDA receptor activation plays a central role in neurotoxicity resulting from activation of AMPA/kainate receptors. It is also apparent from studies documenting the neuroprotective effects of non-NMDA receptor antagonists in animal models of focal and global ischemia that both classes of receptor play important roles in glutamate-induced neurotoxicity (Sheardown et al, 1990;Judge et al, 1991;Balchen and Diemer, 1992;Diemer et al, 1992;Nellgard and Weiloch, 1992;Lippert et al, 1994;Graham et al, 1996).…”

mentioning

confidence: 99%

Domoic Acid Neurotoxicity in Cultured Cerebellar Granule Neurons Is Mediated Predominantly by NMDA Receptors that Are Activated as a Consequence of Excitatory Amino Acid Release

Berman

Murray

1997

Journal of Neurochemistry

121

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The participation of NMDA and non-NMDA receptors in domoic acid-induced neurotoxicity was investigated in cultured rat cerebellar granule cells (CGCs). Neurons were exposed to 300~uML-glutamate or 10 p~M domoate for 2 h in physiologic buffer at 22°Cfollowed by a 22-h incubation in 37°Cconditioned growth media. Excitotoxic injury was monitored as a function of time by measurement of lactate dehydrogenase (LDH) activity in both the exposure buffer and the conditioned media. Glutamate and domoate evoked, respectively, 50 and 65% of the total 24-h increment in LDH efflux after 2 h. Hyperosmolar conditions prevented this early response but did not significantly alter the extent of neuronal injury observed at 24 h. The competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid and the non-NM DA receptor antagonist 2,3-dihydroxy-6-nitro-7sulfamoylbenzo (f )quinoxaline (NBQX) reduced glutamate-induced LDH efflux totals by 73 and 27%, respectively, whereas, together, these glutamate receptor antagonists completely prevented neuronal injury. Domoate toxicity was reduced 65-77% when CGCs were treated with competitive and noncompetitive NMDA receptor antagonists. Unlike the effect on glutamate toxicity, NBQX completely prevented domoate-mediated injury. HPLC analysis of the exposure buffer revealed that domoate stimulates the release of excitatory amino acids (EAAs) and adenosine from neurons. Domoate-stimulated EAA release occurred almost exclusively through mechanisms related to cell swelling and reversal of the glutamate transporter. Thus, whereas glutamate-induced injury is mediated primarily through NMDA receptors, the full extent of neurodegeneration is produced by the coactivation of both NMDA and non-NMDA receptors. Domoateinduced neuronal injury is also mediated primarily through NMDA receptors, which are activated secondarily as a consequence of a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor-mediäted stimulation of EAA efflux. Key Words: Domoic acid-Glutamate-Aspartate-NM DA receptor-a-Amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/ kainate receptor-Excitotoxicity.

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Over-additive protective effect of dizocilpine and NBQX against neuronal damage

Cited by 46 publications

References 27 publications

ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma

ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma

Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones

Domoic Acid Neurotoxicity in Cultured Cerebellar Granule Neurons Is Mediated Predominantly by NMDA Receptors that Are Activated as a Consequence of Excitatory Amino Acid Release

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