Differential Modulation of Glutamatergic Transmission by 3,5-Dibromo-L-phenylalanine

Yarotskyy, Viktor; Glushakov, Alexander V.; Sumners, Colin; Gravenstein, Nikolaus; Dennis, Donn M.; Seubert, Christoph N.; Martynyuk, Anatoly E.

doi:10.1124/mol.104.005983

Cited by 5 publications

(7 citation statements)

References 21 publications

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“…3,5‐DBr‐L‐Phe acts as a partial NMDA receptor agonist. In addition, 3,5‐DBr‐L‐Phe depresses the presynaptic glutamate release and activity of postsynaptic AMPA/kainate receptors (Yarotskyy et al. , 2005).…”

Section: Discussionmentioning

confidence: 99%

“…3,5-DBr-L-Phe acts as a partial NMDA receptor agonist. In addition, 3,5-DBr-L-Phe depresses the presynaptic glutamate release and activity of postsynaptic AMPA/kainate receptors (Yarotskyy et al, 2005). The partial agonism of 3,5-DBr-L-Phe at NMDA receptors should be efficient in the depression of excessive NMDA receptor activity during the acute phase of stroke or during epileptic seizures.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, reduced NMDA receptor activity in schizophrenia or selective targeting of NMDA receptors to depress excessive excitation during the acute phase of stroke or during epileptic seizures may in fact lead to increased glutamate release and further dysregulation of glutamatergic activity. A new polyvalent anti-glutamatergic agent, the halogenated derivative of the aromatic amino acid phenylalanine, 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe), acts as a partial NMDA receptor agonist, reduces glutamate release and depresses the activity of AMPA/kainate receptors (Yarotskyy et al, 2005). Here, we present data that 3,5-DBr-L-Phe reduced neurological deficits and infarct volume in a rat model of stroke caused by intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery (MCA) and depressed seizures in rats induced by pentylenetetrazole (PTZ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of 3,5‐dibromo‐L‐phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit

Cao

Shah

Glushakov

et al. 2009

British J Pharmacology

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Background and purpose: Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit. Experimental approach: 3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit). Key results: Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801. Conclusion and implications:The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Efficacy of 3,5‐dibromo‐L‐phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit

Cao

Shah

Glushakov

et al. 2009

British J Pharmacology

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“…Despite its age, the parent compound is new in the context of glutamate receptors and displayed a rather exceptional pharmacological profile [55]. As shown by electrophysiological experiments conducted on rat cerebrocortical cultured neurons, 46 behaved as a partial agonist acting at postsynaptic NMDA receptors and as a presynaptic agonist suppressing glutamate release.…”

Section: Polyvalent Anti-glutamatergic Agentsmentioning

confidence: 99%

NovelN-methyl-d-aspartate receptor antagonists: a review of compounds patented since 2006

Koller

Urwyler

2010

Expert Opinion on Therapeutic Patents

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The most important recent strategies aiming for inhibition of NMDA receptor-mediated neurotransmission avoid for safety reasons full receptor blockade but allow a low degree of normal receptor function. Approaches pursued by the latest patents comprise blocking the channel with compounds of low affinity, antagonizing receptor activity by highly potent NR2B ligands, partial agonism at the glutamate or glycine-binding site and improvement of pharmacokinetic properties of well established, safe antagonists by deuteration.

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Halogenated aromatic amino acid 3,5-dibromo-d-tyrosine produces beneficial effects in experimental stroke and seizures

et al. 2010

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The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.

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Differential Modulation of Glutamatergic Transmission by 3,5-Dibromo-L-phenylalanine

Cited by 5 publications

References 21 publications

Efficacy of 3,5‐dibromo‐L‐phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit

Efficacy of 3,5‐dibromo‐L‐phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit

NovelN-methyl-d-aspartate receptor antagonists: a review of compounds patented since 2006

Halogenated aromatic amino acid 3,5-dibromo-d-tyrosine produces beneficial effects in experimental stroke and seizures

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