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

Cephalalgia ◽  
2000 ◽  
Vol 20 (6) ◽  
pp. 546-553 ◽  
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.

SB-220453, A Potential Novel Antimigraine Agent, Inhibits Nitric Oxide Release Following Induction of Cortical Spreading Depression in the Anaesthetized Cat

Cephalalgia ◽  
2000 ◽  
Vol 20 (2) ◽  
pp. 92-99 ◽  
Author(s):  
SJ Read ◽  
MI Smith ◽  
AJ Hunter ◽  
N Upton ◽  
AA Parsons
Keyword(s):  
Nitric Oxide ◽  
Median Duration ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Therapeutic Potential ◽  
Field Potential ◽  
Current Field ◽  
Nitric Oxide Release ◽  
Haemodynamic Parameters ◽  
No Release

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.

Nitric oxide and prostaglandins interact to mediate arteriolar dilation during cortical spreading depression

1995 ◽  
Vol 269 (1) ◽  
pp. H176-H181 ◽  
Author(s):  
W. Meng ◽  
D. M. Colonna ◽  
J. R. Tobin ◽  
D. W. Busija
Keyword(s):  
Nitric Oxide ◽  
Cortical Spreading Depression ◽  
Brain Cortex ◽  
Spreading Depression ◽  
Inhibitory Effect ◽  
Onset Latency ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Oxide Synthase ◽  
Arteriolar Diameter

We examined whether blockade of prostaglandin synthesis by indomethacin could attenuate the effect of nitric oxide synthase (NOS) inhibition on cerebral arteriolar dilation during cortical spreading depression (CSD). CSD was induced by microinjection of 5% (670 mM) KCl onto the cerebral cortex of anesthetized adult rabbits. A closed cranial window and intravital microscopy were used to measure pial arteriolar diameter, and NOS activity was determined by the conversion assay of [14C]arginine to [14C]citrulline. CSD dilated pial arterioles by 47 +/- 3% (baseline = 80-88 microns) (n = 21, P < 0.05), and inhibition of NOS by NG-nitro-L-arginine (L-NNA) (15 mg/kg iv) reduced dilation during CSD by over one-half (n = 8, P < 0.05) without altering the onset latency to CSD. After indomethacin administration (15 mg/kg iv), CSD dilated arterioles from 73 +/- 2 to 152 +/- 6 microns (n = 4, P < 0.05). However, after administration of both indomethacin and L-NNA (n = 5), CSD-induced arteriolar dilation was not different from the situation where indomethacin alone was given. Thus indomethacin completely abolished the inhibitory effect of L-NNA on CSD-induced dilation. Administration of L-NNA inhibited NOS activity in brain cortex almost completely (n = 8, P < 0.05), whereas indomethacin itself had no effect (n = 8). In addition, L-NNA inhibited topical acetylcholine (10(-5) M)-induced arteriolar dilation (n = 3, P < 0.05), and this effect was not altered by indomethacin (n = 4). In summary, L-NNA reduced arteriolar dilation during CSD. However, after administration of indomethacin, L-NNA does not reduce CSD-induced arteriolar dilation.

scholarly journals Cerebral Blood Flow Changes during Cortical Spreading Depression are Not Altered by Inhibition of Nitric Oxide Synthesis

1994 ◽  
Vol 14 (6) ◽  
pp. 939-943 ◽  
Author(s):  
Zheng Gang Zhang ◽  
Michael Chopp ◽  
Kenneth I. Maynard ◽  
Michael A. Moskowitz
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Arterial Blood ◽  
Nos Inhibitors ◽  
Before And After ◽  
Male Wistar Rats

CBF increases concomitantly with cortical spreading depression (CSD). We tested the hypothesis that CBF changes during CSD are mediated by nitric oxide (NO). Male Wistar rats (n = 23) were subjected to KCl-induced CSD before and after administration of nitric oxide synthase (NOS) inhibitors N-nitro-l-arginine (L-NNA) or N-nitro-l-arginine methyl ester (L-NAME) and in nontreated animals. CBF, CSD, and mean arterial blood pressure were recorded. Brain NOS activity was measured in vitro in control, L-NNA, and L-NAME-treated rats by the conversion of [3H]arginine to [3H]citrulline. Our data show that the NOS inhibitors did not significantly change regional CBF (rCBF) during CSD, even though cortical NOS activity was profoundly depressed and systemic arterial blood pressure was significantly increased. Our data suggest that rCBF during CSD in rats is not regulated by NO.

Arginine-nitric oxide pathway and cerebrovascular regulation in cortical spreading depression

1995 ◽  
Vol 269 (1) ◽  
pp. H23-H29 ◽  
Author(s):  
M. Fabricius ◽  
N. Akgoren ◽  
M. Lauritzen
Keyword(s):  
Nitric Oxide ◽  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Clinical Importance ◽  
Receptor Activation ◽  
Marked Rise ◽  
Doppler Flowmetry ◽  
Pial Arterioles ◽  
Cerebrovascular Regulation

Nerve cells release nitric oxide (NO) in response to activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. We explored the hypothesis that NO influences the changes of cerebral blood flow (CBF) during cortical spreading depression (CSD), which is known to be associated with NMDA receptor activation. CBF was monitored in parietal cortex by laser-Doppler flowmetry in halothane-anesthetized rats. Under control conditions, CSD induced regular changes of CBF, which consisted of four phases: a brief hypoperfusion before the direct current (DC) shift; a marked CBF rise during the DC shift; followed by a smaller, but protracted increase of CBF; and a prolonged CBF reduction (the oligemia). NO synthase inhibition by intravenous and/or topical application of NG-nitro-L-arginine enhanced the brief initial hypoperfusion, but the CBF increases and the oligemia were unchanged. L-Arginine prevented the development of the prolonged oligemia after CSD but had no influence on the marked rise of CBF during CSD. Animals treated with L-arginine recovered the reduced vascular reactivity to hypercapnia after CSD much faster than control rats. Functional denervation of cortical and pial arterioles by tetrodotoxin accentuated the pre-CSD hypoperfusion and the oligemia but did not affect the CBF increases. The results suggest that NO is important for the changes of cerebrovascular regulation following CSD. The observations may have clinical importance, since CBF changes during migraine may be triggered by CSD.

scholarly journals Flunarizine: a review of its role in migraine prophylaxis

2020 ◽  
Vol 8 (2) ◽  
pp. 786
Author(s):  
M. V. Francis ◽  
Sumit Singh ◽  
Vishal Goyal ◽  
Mukundraj Keny
Keyword(s):  
Weight Gain ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Safety Profile ◽  
Cortical Spreading Depression ◽  
Neurogenic Inflammation ◽  
Spreading Depression ◽  
Channel Blocker ◽  
Migraine Prophylaxis ◽  
Pediatric Migraine

Flunarizine, a potent calcium channel blocker has been used for more than three decades for the prophylactic management of migraine. Theories suggest that flunarizine may act through multiple mechanisms such as inhibition of cortical spreading depression, neurogenic inflammation and channelopathy. Flunarizine is efficacious in the management of various types of migraines such as common, classical, vestibular, abdominal, hemiplegic and pediatric migraine. It has a manageable safety profile with weight gain and drowsiness being commonly reported.

Sign in / Sign up

Export Citation Format

Share Document