Vasodilator Agents and Supracollicular Transection Fail To Inhibit Cortical Spreading Depression in the Cat

Cephalalgia ◽  
1999 ◽  
Vol 19 (6) ◽  
pp. 592-597 ◽  
Author(s):  
H Kaube ◽  
YE Knight ◽  
RJ Storer ◽  
KL Hoskin ◽  
A May ◽  
...  
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Case Reports ◽  
Neurological Deficits ◽  
Visual Aura ◽  
Doppler Flowmetry ◽  
Amyl Nitrite ◽  
Flow Changes ◽  
Speed Of Propagation ◽  
Open Question

It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in α-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that—given CSD probably exists in humans during migraine—spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation.

scholarly journals Hypoxia and Hypotension Transform the Blood Flow Response to Cortical Spreading Depression from Hyperemia into Hypoperfusion in the Rat

2008 ◽  
Vol 28 (7) ◽  
pp. 1369-1376 ◽  
Author(s):  
Inna Sukhotinsky ◽  
Ergin Dilekoz ◽  
Michael A Moskowitz ◽  
Cenk Ayata
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Ischemic Penumbra ◽  
Doppler Flowmetry ◽  
Blood Flow Response ◽  
Flow Response ◽  
Normal Rat ◽  
Cortex Cérébral

Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74 ± 7%) occasionally preceded by a small hypoperfusion (−4 ± 2%). Both hypoxia ( pO2 45 ± 3 mm Hg) and hypotension (blood pressure 42 ± 2 mm Hg) independently augmented this initial hypoperfusion (−14 ± 2% normoxic hypotension; −16 ± 6% hypoxic normotension; −21 ± 5% hypoxic hypotension) and diminished the magnitude of hyperemia (44 ± 10% normoxic hypotension; 43 ± 9% hypoxic normotension; 27 ± 6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs.

scholarly journals Cyclosporine A, FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression

2011 ◽  
Vol 31 (7) ◽  
pp. 1588-1598 ◽  
Author(s):  
Henning Piilgaard ◽  
Brent M Witgen ◽  
Peter Rasmussen ◽  
Martin Lauritzen
Keyword(s):  
Cyclosporine A ◽  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Mitochondrial Permeability Transition ◽  
Neurovascular Coupling ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Doppler Flowmetry ◽  
Electrocortical Activity

Cortical spreading depression (CSD) is associated with mitochondrial depolarization, increasing intracellular Ca2+, and the release of free fatty acids, which favor opening of the mitochondrial permeability transition pore (mPTP) and activation of calcineurin (CaN). Here, we test the hypothesis that cyclosporine A (CsA), which blocks both mPTP and CaN, ameliorates the persistent reduction of cerebral blood flow (CBF), impaired vascular reactivity, and a persistent rise in the cerebral metabolic rate of oxygen (CMRO2) following CSD. In addition to CsA, we used the specific mPTP blocker NIM811 and the specific CaN blocker FK506. Cortical spreading depression was induced in rat frontal cortex. Electrocortical activity was recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension with polarographic microelectrodes. Electrocortical activity, basal CBF, CMRO2, and neurovascular and neurometabolic coupling were unaffected by all three drugs under control conditions. NIM811 augmented the rise in CBF observed during CSD. Cyclosporine A and FK506 ameliorated the persistent decrease in CBF after CSD. All three drugs prevented disruption of neurovascular coupling after CSD; the rise in CMRO2 was unchanged. Our data suggest that blockade of mPTP formation and CaN activation may prevent persistent CBF reduction and vascular dysfunction after CSD.

scholarly journals Persistent Increase in Oxygen Consumption and Impaired Neurovascular Coupling after Spreading Depression in Rat Neocortex

2009 ◽  
Vol 29 (9) ◽  
pp. 1517-1527 ◽  
Author(s):  
Henning Piilgaard ◽  
Martin Lauritzen
Keyword(s):  
Cortical Spreading Depression ◽  
Vascular Reactivity ◽  
Spreading Depression ◽  
Acute Hypoxia ◽  
Ion Homeostasis ◽  
Neurovascular Coupling ◽  
Doppler Flowmetry ◽  
Neurometabolic Coupling ◽  
Rat Neocortex ◽  
Cortical Electrical Activity

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is the mechanism of migraine, and involved in progressive neuronal injury in stroke and head trauma. Here we tested the hypothesis that single episodes of CSD induced acute hypoxia, and prolonged impairment of neurovascular and neurometabolic coupling. Cortical spreading depression was induced in rat frontal cortex, whereas cortical electrical activity and local field potentials (LFPs) were recorded by glass microelectrodes, cerebral blood flow (CBF) by laser—Doppler flowmetry, and tissue oxygen tension (tpO2) with Polarographic microelectrodes. Cortical spreading depression increased cerebral metabolic rate of oxygen (CMRO2) by 71% ± 6.7% and CBF by 238% ± 48.1% for 1 to 2 mins. For the following 2 h, basal tpO2 and CBF were reduced whereas basal CMRO2 was persistently elevated by 8.1% ± 2.9%. In addition, within first hour after CSD we found impaired neurovascular coupling (LFP versus CBF), whereas neurometabolic coupling (LFP versus CMRO2) remained unaffected. Impaired neurovascular coupling was explained by both reduced vascular reactivity and suppressed function of cortical inhibitory interneurons. The protracted effects of CSD on basal CMRO2 and neurovascular coupling may contribute to cellular dysfunction in patients with migraine and acutely injured cerebral cortex.

scholarly journals Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

2016 ◽  
Vol 37 (3) ◽  
pp. 1060-1068 ◽  
Author(s):  
Helaine Gariepy ◽  
Jun Zhao ◽  
Dan Levy
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Selective Inhibition ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Later Phase ◽  
Cox 1

Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2 (TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2 followed by a later phase, mediated by COX-2 and PGF2alpha.

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 Systemic Nitric Oxide Synthase Inhibition Does Not Affect Brain Oxygenation during Cortical Spreading Depression in Rats: A Noninvasive Near-Infrared Spectroscopy and Laser-Doppler Flowmetry Study

1996 ◽  
Vol 16 (6) ◽  
pp. 1100-1107 ◽  
Author(s):  
Tilo Wolf ◽  
Ute Lindauer ◽  
Hellmuth Obrig ◽  
Jens Dreier ◽  
Tobias Back ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Infrared Spectroscopy ◽  
Nitric Oxide Synthase ◽  
Near Infrared Spectroscopy ◽  
Laser Doppler Flowmetry ◽  
Cortical Spreading Depression ◽  
Near Infrared ◽  
Spreading Depression ◽  
Doppler Flowmetry ◽  
Oxide Synthase

Cortical spreading depression (CSD) has been implicated in the migraine aura and in stroke. This study demonstrates near-infrared spectroscopy (NIRS) for the first time as capable of noninvasive on-line detection of CSD in the pentobarbital-anesthetized rat. CSD was accompanied by a brief and rapid increase of regional CBF (by laser-Doppler flowmetry) to 200–400% baseline. NIRS demonstrates that this hyperperfusion is associated with concentration increases of oxyhemoglobin, while deoxyhemoglobin decreases. Simultaneously, oxygen partial pressure, measured on the brain surface with a solid-state Polarographic probe, was shown to be raised by at least 14 mm Hg during CSD. Oxygen-dependent phosphorescence life-time quenching measurements confirmed this finding. NIRS data on cytochrome aa3, however, showed a CSD-related shift toward a more reduced state, despite raised blood oxygenation. This may suggest either limited O2 transport from the blood to mitochondria or decreased oxygen utilization during CSD as supposed by theories about compartmentalization of energy metabolism favoring glycolytic rather than aerobic energy supply during CSD. However, the data on cytochrome aa3, warrant caution and are discussed critically. Nitric oxide synthase inhibition by systemic application of N′-nitro-l-arginine had no significant effect on the perfusion response or the tissue Po2 during CSD. During most CSD episodes, a brief decrease in MABP by 4–8 mm Hg was noted that might be caused by functional decortication during CSD.

Subcortical Cerebral Blood Flow and Metabolic Changes Elicited by Cortical Spreading Depression in Rat

Cephalalgia ◽  
1992 ◽  
Vol 12 (3) ◽  
pp. 137-141 ◽  
Author(s):  
Sima Mraovitch ◽  
Yolande Calando ◽  
Peter J Goadsby ◽  
Jacques Seylaz
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Contralateral Side ◽  
Local Cerebral Blood Flow ◽  
Doppler Flowmetry ◽  
Subcortical Regions ◽  
First Time ◽  
Cortical Perfusion

Changes in cerebral cortical perfusion (CBFLDF), local cerebral blood flow (ICBF) and local cerebral glucose utilization (ICGU) elicited by unilateral cortical spreading depression (SD) were monitored and measured in separate groups of rats anesthetized with a-chloralose. CBFLDF was recorded with laser Doppler flowmetry, while ICBF and ICGU were measured by the quantitative autoradiographic [14C]iodoantipyrine and [14C]-2-deoxyglucose methods, respectively. SD elicited a wave of hyperemia after a latency of 2 to 3 min followed by an oligemic phase. Ninety minutes following the onset of SD cortical (frontal, parietal and occipital) ICBF and ICGU were essentially the same as on the contralateral side and in sham-treated rats. However, alteration in the ICBF and ICGU in upper and lower brainstem persisted. The present results demonstrate, for the first time, that long-lasting cerebrovascular and metabolic alterations take place within the subcortical regions following SD. These regions provide an attractive site to integrate observations in man concerning spreading depression and the aura of migraine with the other features of the syndrome.

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