scholarly journals Effect of serotonin depletion on cortical spreading depression evoked cerebrovascular changes

2010 ◽  
Vol 4 (5) ◽  
pp. 731-738 ◽  
Author(s):  
Supang Maneesri le Grand ◽  
Weera Supornsilpchai ◽  
Chonlawan Saengjaroentham ◽  
Juntima Pleumsamran ◽  
Anan Srikiatkhachorn
Keyword(s):  
Cortical Neurons ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Control Group ◽  
Cerebral Microvessels ◽  
Doppler Flowmetry ◽  
Pathological Conditions ◽  
Migraine Pathophysiology ◽  
The Relationship ◽  
Cerebral Cortical Blood Flow

Abstract Background: The cortical spreading depression (CSD) is a phenomenon associated with several pathological conditions including migraine. It can induce alterations in both neural and vascular compartments. Serotonin (5-HT) depletion is known as a condition involved in migraine pathophysiology. The hyper-excitability of the cortical neurons to the CSD activation in the low 5-HT state has been previously reported. However, the cerebrovascular responses to CSD activation in this condition have never been studied yet. Objectives: Determine the effect of 5-HT depletion on the cerebrovascular responses to CSD activation. Methods: Wistar rats (weighing 250-300 grams) were divided into three groups: control, CSD, and low 5-HT with CSD group (five rats per group). To induce the low 5-HT state, the para-chlorophenylalanine was injected intraperitoneally into the rats three days before the experiment. CSD was induced by the application of solid KCl (3 mg) on the parietal cortex. NaCl instead of KCl was applied to the control group. Cerebral cortical blood flow was monitored using Laser Doppler flowmetry. The ultrastructure of cerebral microvessels was examined using electron microscopy to determine the cerebral microcirculatory responses to CSD. Results: Depletion of serotonin induced a significant increase in the peak amplitude of CSD-evoked cerebral hyperaemia. This condition also enhanced the development of CSD-induced endothelial pinocytosis and microvillus formation in cerebrocortical microvessels. Conclusion: 5-HT was an important neurotransmitter involved in the control of cerebrovascular responses to CSD activation. The hypersensitivity of the cerebrovascular responses observed in the 5-HT depleted state may explain the relationship between headache and 5-HT depletion.

scholarly journals Exploring the role of microglia in cortical spreading depression in neurological disease

2017 ◽  
Vol 37 (4) ◽  
pp. 1182-1191 ◽  
Author(s):  
Mamoru Shibata ◽  
Norihiro Suzuki
Keyword(s):  
Cortical Neurons ◽  
Neurological Disease ◽  
Cortical Spreading Depression ◽  
Microglial Activation ◽  
Spreading Depression ◽  
Traumatic Injury ◽  
The Relationship ◽  
The Brain ◽  
Microglial Development

Microglia play a pivotal role in innate immunity in the brain. During development, they mature from myeloerythroid progenitor cells in the yolk sac and colonize the brain to establish a resident population of tissue macrophages. In the postnatal brain, they exert phagocytosis and induce inflammatory response against invading pathogens. Microglia also act as guardians of brain homeostasis by surveying the microenvironment using motile processes. Cortical spreading depression (CSD) is a slowly propagating (2–5 mm/min) wave of rapid, near-complete depolarization of neurons and astrocytes followed by a period of electrical suppression of a distinct population of cortical neurons. Not only has CSD been implicated in brain migraine aura, but CSD-like events have also been detected in stroke and traumatic injury. CSD causes a considerable perturbation of the ionic environment in the brain, which may be readily detected by microglia. Although CSD is known to activate microglia, the role of microglial activation in CSD-related neurological disorders remains poorly understood. In this article, we first provide an overview of microglial development and the multiple functions of microglia. Then, we review existing data on the relationship between microglia and CSD and discuss the relevance of CSD-induced microglial activation in neurological disease.

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 In Vivo Uptake of [3H]Nimodipine into Brain during Cortical Spreading Depression

1997 ◽  
Vol 17 (5) ◽  
pp. 586-590 ◽  
Author(s):  
Sachiko Osuga ◽  
Antoine M. Hakim ◽  
Hitoshi Osuga ◽  
Matthew J. Hogan
Keyword(s):  
Rat Brain ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Control Group ◽  
Similar Measurement ◽  
Contralateral Hemisphere ◽  
Radiotracer Uptake ◽  
Uptake Studies ◽  
In Vivo Uptake

We report autoradiographic measurements of the in vivo uptake of [3H]nimodipine during the nonischemic depolarization of cortical spreading depression (CSD) in rat brain. [3H]Nimodipine uptake in brain was determined regionally in rats undergoing CSD (n = 8) and was significantly increased in cortex (14 ± 7%) and hippocampus (10 ± 6%) on the stimulated side relative to the contralateral hemisphere when compared with the same measurements in a control group (n = 8). A similar measurement using the physiologically inert radiotracer [14C]iodoantipyrine to control for potential effects of CSD on radioligand distribution showed a minimal increase (2.4 ± 0.7%) of radiotracer uptake in cortex after CSD. This increase was significantly less than that observed in the [3H]nimodipine uptake studies. We hypothesize that increased in vivo [3H]nimodipine uptake in CSD identifies regions of depolarization and thus infers activation of the L-type voltage sensitive calcium channels.

scholarly journals High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression

2016 ◽  
Vol 37 (3) ◽  
pp. 890-901 ◽  
Author(s):  
Tsubasa Takizawa ◽  
Mamoru Shibata ◽  
Yohei Kayama ◽  
Toshihiko Shimizu ◽  
Haruki Toriumi ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Cortical Spreading Depression ◽  
Microglial Activation ◽  
Spreading Depression ◽  
High Mobility ◽  
High Mobility Group ◽  
Migraine Aura ◽  
Double Knockout ◽  
Activated Microglia ◽  
Important Mediator

Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1–TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

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.

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 Combined onabotulinumtoxinA/atogepant treatment blocks activation/sensitization of high-threshold and wide-dynamic range neurons

Cephalalgia ◽  
2020 ◽  
pp. 033310242097050
Author(s):  
Agustin Melo-Carrillo ◽  
Andrew M Strassman ◽  
Aaron J Schain ◽  
Aubrey Manack Adams ◽  
Mitchell F Brin ◽  
...  
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Dynamic Range ◽  
Combined Treatment ◽  
Control Group ◽  
High Threshold ◽  
Wide Dynamic Range ◽  
C Fibers ◽  
Calcitonin Gene ◽  
Wide Dynamic Range Neurons

Background OnabotulinumtoxinA and agents that block calcitonin gene‒receptor peptide action have both been found to have anti-migraine effects, but they inhibit different populations of meningeal nociceptors. We therefore tested the effects of combined treatment with onabotulinumtoxinA and the calcitonin gene‒receptor peptide antagonist atogepant on activation/sensitization of trigeminovascular neurons by cortical spreading depression. Material and methods Single-unit recordings were obtained of high-threshold and wide-dynamic-range neurons in the spinal trigeminal nucleus, and cortical spreading depression was then induced in anesthetized rats that had received scalp injections of onabotulinumtoxinA 7 days earlier and intravenous atogepant infusion 1 h earlier. The control group received scalp saline injections and intravenous vehicle infusion. Results OnabotulinumtoxinA/atogepant pretreatment prevented cortical spreading depression-induced activation and sensitization in both populations (control: Activation in 80% of high-threshold and 70% of wide-dynamic-range neurons, sensitization in 80% of high-threshold and 60% of wide-dynamic-range neurons; treatment: activation in 10% of high-threshold and 0% of wide-dynamic-range neurons, sensitization in 0% of high-threshold and 5% of wide-dynamic-range neurons). Discussion We propose that the robust inhibition of high-threshold and wide-dynamic-range neurons by the combination treatment was achieved through dual blockade of the Aδ and C classes of meningeal nociceptors. Combination therapy that inhibits meningeal C-fibers and prevents calcitonin gene‒receptor peptide from activating its receptors on Aδ-meningeal nociceptors may be more effective than a monotherapy in reducing migraine days per month in patients with chronic migraine.

Sign in / Sign up

Export Citation Format

Share Document