Capillary Endothelial Na<sup>+</sup>, K<sup>+</sup>, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

Harrington, Michael G.; Fonteh, Alfred N.; Arakaki, Xianghong; Cowan, Robert P.; Ecke, Laurel E.; Foster, Hailey; Hühmer, Andreas; Biringer, Roger G.

doi:10.1111/j.1526-4610.2009.01551.x

Cited by 25 publications

(39 citation statements)

References 192 publications

(144 reference statements)

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“…In addition, our recent studies suggest the Na + -K + -ATPase at the blood-brain barrier may be more labile in migraineurs (Arakaki et al, 2013;Harrington et al, 2010), and this transporter is modulated by neurotransmitters such as serotonin. Brain alpha2 type Na + -K + -ATPase activity was significantly increased by 5-HT (Antonelli et al, 1998), thus an additional role for Na + -K + -ATPase involvement in the rat model requires further study.…”

Section: Discussionmentioning

confidence: 99%

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Arakaki¹,

Galbraith²,

Pikov³

et al. 2014

Brain Research

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Migraine symptoms often include auditory discomfort. Nitroglycerin (NTG)-triggered central sensitization (CS) provides a rodent model of migraine, but auditory brainstem pathways have not yet been studied in this example. Our objective was to examine brainstem auditory evoked potentials (BAEPs) in rat CS as a measure of possible auditory abnormalities. We used four subdermal electrodes to record horizontal (h) and vertical (v) dipole channel BAEPs before and after injection of NTG or saline. We measured the peak latencies (PLs), interpeak latencies (IPLs), and amplitudes for detectable waveforms evoked by 8, 16, or 32 KHz auditory stimulation. At 8 KHz stimulation, vertical channel positive PLs of waves 4, 5, and 6 (vP4, vP5, and vP6), and related IPLs from earlier negative or positive peaks (vN1-vP4, vN1-vP5, vN1-vP6; vP3-vP4, vP3-vP6) increased significantly 2 hours after NTG injection compared to the saline group. However, BAEP peak amplitudes at all frequencies, PLs and IPLs from the horizontal channel at all frequencies, and the vertical channel stimulated at 16 and 32 KHz showed no significant/consistent change. For the first time in the rat CS model, we show that BAEP PLs and IPLs ranging from putative bilateral medial superior olivary nuclei (P4) to the more rostral structures such as the medial geniculate body (P6) were prolonged 2 hours after NTG administration. These BAEP alterations could reflect changes in neurotransmitters and/or hypoperfusion in the midbrain. The similarity of our results with previous human studies further validates the rodent CS model for future migraine research.

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Section: Discussionmentioning

confidence: 99%

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Arakaki¹,

Galbraith²,

Pikov³

et al. 2014

Brain Research

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“…An alternative route of K ϩ dissipation may be the capillary network, which densely penetrates the brain tissue with an average intercapillary distance of ϳ50 m. Therefore, the capillary network is the largest sink within the brain tissue that can contribute to the vascular clearance of [ (456,457). In summary, direct vascular regulation of extracellular ionic milieu (i.e., vascular clearance of [K ϩ ] o ) has implications for not only SD recovery and brain injury states, but also for migraine triggers (182). Lastly, it is worth noting that the perivascular space, suggested as a potential route of cerebral waste clearance through bulk CSF flow (210,211), may also contribute to [K ϩ ] o clearance during SD.…”

Section: Role Of Vasculature In Spreading Depression Recoverymentioning

confidence: 96%

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Ayata

Lauritzen

2015

Physiological Reviews

458

600

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Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

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“…Physiological fluctuations of all NKAT regulators in blood, many known to be involved in migraine, were monitored by receptors on the luminal wall of brain CECs; signals then transduced to their abluminal NKATs that alter brain extracellular sodium ([Na + ]e) and potassium ([K + ] e ). They proposed a theoretical mechanism for aura and migraine when NKAT activity shifts outside normal limits: (1) CEC NKAT activity below a lower limit increases [K + ] e , facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates [Na + ] e , increases neuronal excitability, and causes migraine; (3) Migraine-without-aura may arise from CEC NKAT over-activity without requiring a prior decrease in activity and its consequent spreading depression; (4) migraine triggers disturb, and treatments improve, CEC NKAT homeostasis; (5) CEC NKAT-induced regulation of neural and vasomotor excitability coordinates vascular and neuronal activities, and includes occasional pathology from CEC NKAT-induced apoptosis or cerebral infarction [81]. As mentioned above the NKA is an ion-translocating transmembrane protein that actively maintains the electrochemical gradients for Na + and K + across the plasma membrane.…”

Section: Pathophysiological Relevance Of Nkamentioning

confidence: 99%

Na+, K+-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions

Suhail

2010

J Clin Med Res

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The Na+, K+-ATPase (NKA) is an ubiquitous enzyme consisting of α, β and γ subunits, and is responsible for the creation and maintenance of the Na+ and K+ gradients across the cell membrane by transporting 3 Na+ out and 2 K+ into the cell. Sodium pump regulation is tissue as well as isoform specific. Intracellular messengers differentially regulate the activity of the individual NKA isozymes. Regulation of specific NKA isozymes gives cells the ability to precisely coordinate NKA activity to their physiological requirements. It is the only known receptor for the cardiac glycosides used to treat congestive heart failure and cardiac arrhythmias. Endogenous ligands structurally similar to cardiac glycosides may act as natural regulators of the sodium pump in heart and other tissues. Identification of naturally occurring regulators of NKA could initiate the discovery of new hormone-like control systems involved in the etiology of selected disease processes, hence the importance of understanding the relation of the sodium pump and its ligands to disease. Diabetes has a marked effect on the metabolism of a variety of tissues and because the NKA is critical for the membrane potential and many transports, a change in its activity in diabetes would have profound consequence in these tissues. NKA is also involved in hypertension, salt balance, cardiovascular and renal disorders, sperm capacitation, cell volume regulation, apoptosis, rheumatoid arthritis, sepsis, neurological disorders, lung edema clearance and preeclampsia. NKA activity and expression in the collecting duct of kidney are modulated physiologically by hormones like aldosterone, vasopressin, and insulin. NKA enzyme activity and subunit levels are reduced in carcinoma, NKA-β levels were highly reduced in an invasive form of human renal clear cell carcinoma, androgen-dependent prostate cancer, in early stages of urothelial cancer, as well as in poorly differentiated, highly motile carcinoma cell lines obtained from various tissues suggesting a functional link between reduced NKA-β expression and cancer progression. It could be a target for the development of anticancer drugs as it serves as a signal transducer, it is a player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers.KeywordsNa+, K+-ATPase (NKA); Cardiotonic steroids (CTS); Diabetes; Hypertension; Cardiovascular and renal disorders; Signal transducer; Anticancer drugs

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Capillary Endothelial Na⁺, K⁺, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

Cited by 25 publications

References 192 publications

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Na+, K+-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions

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Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

Cited by 25 publications

References 192 publications

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Na+, K+-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions

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Capillary Endothelial Na⁺, K⁺, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology