Effects of Pan- and Subtype-Selective N-Methyl-d-aspartate Receptor Antagonists on Cortical Spreading Depression in the Rat: Therapeutic Potential for Migraine

Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine pathophysiology. SB-220453 represents a mechanistically novel, well-tolerated class of compounds which may have therapeutic potential in the treatment of conditions associated with neuronal hyperexcitability and inflammation. The aim of the present study was to investigate the effects of SB-220453 on the nitric oxide (NO) release associated with SD in the anaesthetized cat. In vehicle treated animals, KCl application for 6 min to the cortical suface produced repeated changes in extracellular direct current field potential with associated NO release. This activity was sustained for a median duration of 55 min (25–75% range, 32–59 min) and 59 min (25–75% range, 34–59 min), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-related inhibition of this activity and at the highest dose tested, the median duration of changes in extracellular field potential and NO release were reduced to 4 min (25–75% range, 4–5min) and 5 min (25–75% range, 5–5min), respectively. No effect was observed on basal systemic haemodynamic parameters or resting cerebral laser Doppler blood flux at any of the doses of SB-220453 tested. SB-220453 therefore represents a novel compound to assess the potential benefit of inhibiting SD associated nitric oxide release in neurological disease.

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Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms21041269 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1269 ◽

Cited By ~ 1

Author(s):

Fan Bu ◽

Lingdi Nie ◽

John P Quinn ◽

Minyan Wang

Keyword(s):

Mouse Brain ◽

Protein Interactions ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Regulatory Mechanism ◽

Brain Slices ◽

Pannexin 1 ◽

Migraine Headaches ◽

Aspartate Receptor ◽

Channel Opening

Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K+ to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A–receptor antagonist, NVP–AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK–Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP–AAM077 reduced elevation of ipsilateral SFK–Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.

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Increased extracellular potassium concentration reduces the efficacy of N-methyl-D-aspartate receptor antagonists to block spreading depression in human and rat brain slices

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0470 ◽

2005 ◽

Vol 25 (1_suppl) ◽

pp. S470-S470

Author(s):

Gabor C Petzold ◽

Stephan Haack ◽

Dirk Megow ◽

Katharina Buchheim ◽

Uwe Heinemann ◽

...

Keyword(s):

Rat Brain ◽

Spreading Depression ◽

Potassium Concentration ◽

Brain Slices ◽

Extracellular Potassium ◽

Receptor Antagonists ◽

Extracellular Potassium Concentration ◽

Aspartate Receptor

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EHMTI-0018. CGRP receptor antagonists attenuate pain behavior induced by cortical spreading depression in freely moving rats

The Journal of Headache and Pain ◽

10.1186/1129-2377-15-s1-f6 ◽

2014 ◽

Vol 15 (S1) ◽

Cited By ~ 1

Author(s):

A Filiz ◽

N Tepe ◽

E Boran ◽

E Sajedeh ◽

E Lars ◽

...

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Pain Behavior ◽

Cgrp Receptor ◽

Receptor Antagonists ◽

Freely Moving Rats ◽

Cgrp Receptor Antagonists ◽

Freely Moving

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Repetitive Cortical Spreading Depression in a Gyrencephalic Feline Brain: Inhibition by the Novel Benzoylamino-Benzopyran SB-220453

Cephalalgia ◽

10.1046/j.1468-2982.2000.00092.x ◽

2000 ◽

Vol 20 (6) ◽

pp. 546-553 ◽

Cited By ~ 53

Author(s):

MI Smith ◽

SJ Read ◽

WN Chan ◽

M Thompson ◽

AJ Hunter ◽

...

Keyword(s):

Nitric Oxide ◽

Cortical Spreading Depression ◽

Neurogenic Inflammation ◽

Spreading Depression ◽

Therapeutic Potential ◽

The Novel ◽

Unknown Mechanism ◽

Nitric Oxide Release ◽

Metabolic Coupling ◽

Marked Inhibition

Transient cortical depolarization is implicated in the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide release via a novel but unknown mechanism. This study further investigates the effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally 90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c. potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated animals ( n = 7), a brief exposure (6 min) to KCl induced a median (25–75% range) number of five (four to six) and three (two to four) depolarizations over a duration of 55 min (32–59 min) and 51 min (34–58 min) in the SG and MG, respectively. SB-220453 produced dose-related inhibition of the number of events and period of repetitive SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation but had no effect on resting haemodynamics. However, when SD events were observed in the presence of SB-220453, it had no effect on metabolic coupling. These results show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like activity in migraine.

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ChemInform Abstract: Subtype-Selective N-Methyl-D-aspartate Receptor Antagonists: Synthesis and Biological Evaluation of 1-(Heteroarylalkynyl)-4-benzylpiperidines.

ChemInform ◽

10.1002/chin.200101152 ◽

2001 ◽

Vol 32 (1) ◽

pp. no-no

Author(s):

Jon L. Wright ◽

et al. et al.

Keyword(s):

Biological Evaluation ◽

Receptor Antagonists ◽

Aspartate Receptor ◽

Subtype Selective ◽

Synthesis And Biological Evaluation

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Comprehensive QSAR studies reveal structural insights into the NR2B subtype selective benzazepine derivatives as N-Methyl- -Aspartate receptor antagonists

Journal of Molecular Structure ◽

10.1016/j.molstruc.2019.07.068 ◽

2019 ◽

Vol 1197 ◽

pp. 617-627 ◽

Cited By ~ 2

Author(s):

Vishal P. Zambre ◽

Rajesh B. Patil ◽

Jaiprakash N. Sangshetti ◽

Sanjay D. Sawant

Keyword(s):

Receptor Antagonists ◽

Qsar Studies ◽

Aspartate Receptor ◽

Methyl Aspartate ◽

Subtype Selective ◽

Structural Insights

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Sarcoma family kinase activity is required for cortical spreading depression

Cephalalgia ◽

10.1177/0333102417748572 ◽

2017 ◽

Vol 38 (11) ◽

pp. 1748-1758 ◽

Cited By ~ 4

Author(s):

Fan Bu ◽

Yan Wang ◽

Liwen Jiang ◽

Dongqing Ma ◽

John P Quinn ◽

...

Keyword(s):

Cortical Spreading Depression ◽

Spreading Depression ◽

Kinase Activity ◽

Brain Slices ◽

Inhibitory Effect ◽

Optical Signal ◽

Migraine Aura ◽

Aspartate Receptor ◽

Kinase Phosphorylation ◽

Pharmacological Manipulations

Objectives Sarcoma family kinase activity is associated with multiple diseases including ischemia and cancer; however, its role in the mechanism of migraine aura has been less well characterised. This study aims to investigate whether sarcoma family kinase is required for cortical spreading depression. Methods Cortical spreading depression was induced by topical application of K+ to the cerebral cortex and was monitored using electrophysiology in rats, and intrinsic optical signal in mouse brain slices. Drugs were perfused into the contralateral cerebral ventricle for pharmacological manipulations in rats. Western blot analysis was used for detecting the level of phosphorylated, and total, sarcoma family kinase in the ipsilateral cortex of rats. Key results The data demonstrate that a single cortical spreading depression in rats induced ipsilateral cortical sarcoma family kinase phosphorylation at the Y416 site. Deactivation of sarcoma family kinase by its inhibitor (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1 H-pyrazolo[3,4- dpyrimidin-4-amine) suppressed the elevated enzyme activity and cortical susceptibility to cortical spreading depression. Interestingly, the inhibitory effect of the N-methyl-D-aspartate receptor antagonist NVP-AAM077 on cortical spreading depression was reversed by the sarcoma family kinase activator pYEEI (EPQY(PO3H2)EEEIPIYL), suggesting a link between this enzyme and N-methyl-D-aspartate receptors. Similarly, after deactivation of sarcoma family kinase, a reduction of sarcoma family kinase phosphorylation and cortical susceptibility to cortical spreading depression was observed with NVP-AAM077. Conclusions We conclude that activation of sarcoma family kinase is required for cortical spreading depression, and this process is regulated by recruiting N-methyl-D-aspartate receptors. This study provides novel insight for sarcoma family kinase function in the mechanism of migraine aura.

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