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

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.28 ◽

2011 ◽

Vol 31 (7) ◽

pp. 1588-1598 ◽

Cited By ~ 23

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.1.h23 ◽

1995 ◽

Vol 269 (1) ◽

pp. H23-H29 ◽

Cited By ~ 11

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.

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Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.191 ◽

2010 ◽

Vol 31 (1) ◽

pp. 17-35 ◽

Cited By ~ 422

Author(s):

Martin Lauritzen ◽

Jens Peter Dreier ◽

Martin Fabricius ◽

Jed A Hartings ◽

Rudolf Graf ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurological Disorders ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Neuronal Damage ◽

Ion Homeostasis ◽

Large Body ◽

Treatment Strategies ◽

Pathophysiological Mechanism

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.35 ◽

2008 ◽

Vol 28 (7) ◽

pp. 1369-1376 ◽

Cited By ~ 56

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.

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Cortical spreading depression produces long-term disruption of activity-related changes in cerebral blood volume and neurovascular coupling

Journal of Biomedical Optics ◽

10.1117/1.1852556 ◽

2005 ◽

Vol 10 (1) ◽

pp. 011004 ◽

Cited By ~ 24

Author(s):

Michael Guiou ◽

Sameer Sheth ◽

Masahito Nemoto ◽

Melissa Walker ◽

Nader Pouratian ◽

...

Keyword(s):

Blood Volume ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Cerebral Blood Volume ◽

Neurovascular Coupling

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

Cephalalgia ◽

10.1046/j.1468-2982.1999.019006592.x ◽

1999 ◽

Vol 19 (6) ◽

pp. 592-597 ◽

Cited By ~ 15

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.

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Assessment of neurovascular coupling and cortical spreading depression in mixed mouse models of atherosclerosis and Alzheimer’s disease

eLife ◽

10.7554/elife.68242 ◽

2022 ◽

Vol 11 ◽

Author(s):

Osman Shabir ◽

Ben Pendry ◽

Llywelyn Lee ◽

Beth Eyre ◽

Paul S Sharp ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Spreading Depression ◽

Mixed Model ◽

Spreading Depression ◽

Neurovascular Coupling ◽

Cardiovascular Comorbidities ◽

Neurological Conditions ◽

Electrode Insertion ◽

The Brain

Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in mouse preparations that modelled Alzheimer’s disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9 and 12 m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, altered levels of oxyhaemoglobin and deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3 x increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimer’s-related amyloid-plaques.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16650217 ◽

2016 ◽

Vol 37 (3) ◽

pp. 1060-1068 ◽

Cited By ~ 10

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.

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