Ouabain Binding in the Human Brain

Harik, Sami I.

doi:10.1001/archneur.1989.00520450021013

Cited by 30 publications

(5 citation statements)

References 27 publications

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“…It is consistent with this concept that pyruvate dehydrogenase activity is compromised in Alzheimer brains [418][419]. A reduction of Na + ,K + -ATPase activity [420] could also mainly be an astrocytic effect, since noradrenaline stimulates Na + ,K + -ATPase activity in cultured astrocytes with little effect on cultured neurons [22].…”

Section: Alzheimer's Diseasesupporting

confidence: 72%

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Hertz¹,

Chen²,

Gibbs³

et al. 2004

CDTCNSND

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Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodal, long-term memory, which is reinforced by β-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occurs at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

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Section: Alzheimer's Diseasesupporting

confidence: 72%

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Hertz¹,

Chen²,

Gibbs³

et al. 2004

CDTCNSND

View full text Add to dashboard Cite

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“…Additionally, the neuron‐specific α3 subunit of brain Na,K‐ATPase is reduced. 69–72 The α‐ketoglutarate dehydrogenase enzyme complex, which catalyzes the conversion of α‐ketoglutarate to succinyl‐coenzyme A in the tricarboxylic acid cycle within mitochondria, has been found to be reduced in FAD involving a mutation causing overproduction of amyloid β peptide, but in both affected and unaffected brain regions. 73 Its reduction in the unaffected regions may be related to increased expression of this peptide.…”

Section: Discussionmentioning

confidence: 99%

Functional Brain Imaging in the Resting State and during Activation in Alzheimer's Disease: Implications for Disease Mechanisms Involving Oxidative Phosphorylation

Rapoport

1999

Annals of the New York Academy of Sciences

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In vivo brain imaging of patients with Alzheimer's disease (AD) using positron emission tomography (PET) demonstrates progressive reductions in resting-state brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. During cognitive or psychophysical stimulation, blood flow and metabolism in the affected regions can increase to the same extent in mildly demented AD patients as in age-matched controls, suggesting that energy delivery is not rate limiting. Activation declines with dementia severity, and is markedly reduced in severely demented patients. These results suggest that there is an initial "normal" functionally-responsive stage in AD, followed by a late less responsive stage. Studies of biopsied and postmortem brain indicate that the initial stage is accompanied by selective and potentially reversible down-regulation of the brain enzymes, including cytochrome oxidase, which mediate mitochondrial oxidative-phosphorylation.

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“…Measurements of $H-ouabain binding to microsomes obtained from brain cortex of patients with Alzheimer's disease show a decrease of 40 % [131], and in microsomes from the basal ganglia of patients with Huntington's chorea a decrease of 50 % has been reported [132]. Such large reductions in the Na + ,K + -pump capacity are most likely to be associated with functional impairment of the tissue, but it cannot be discerned whether they are primary or secondary to the overall pathological process.…”

Section: Central Nervous System Disordersmentioning

confidence: 99%

Clinical and therapeutic significance of the Na+,K+ pump*

Clausen¹

1998

Clinical Science

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1. The Na+,K+-ATPase or Na+,K+-pump, mediating the active transport of Na+ and K+, which was first identified 40 years ago, is a central target for acute and long-term regulation, as well as for therapeutic intervention. Acute stimulation of the Na+,K+-pump in skeletal muscle by insulin, catecholamines, beta2-agonists or theophylline increases the intracellular uptake of K+ and accounts for the hypokalaemia elicited by these agents. Conversely, digitalis intoxication elicits hyperkalaemia via acute inhibition of the Na+, K+-pump. 2. Simple and accurate methods have been developed for the quantification of the total concentration of Na+,K+-pumps in small (0.5-5 mg) fresh or frozen biopsies of human skeletal muscle, myocardium or other tissues. This has allowed the identification of several long-term regulatory changes in the concentration of this transport system in human tissues. In skeletal muscle, upregulation is induced by training, thyroid hormones or glucocorticoids. Downregulation is seen in hypothyroidism, cardiac insufficiency, myotonic dystrophy, McArdle disease, K+ deficiency and after muscle inactivity. 3. Since the skeletal muscles contain one of the major pools of Na+,K+-pumps, these changes are important for the ability to counterregulate the hyperkalaemia elicited by exercise or the ingestion of K+. Moreover, downregulation or inhibition of the Na+, K+-pumps in skeletal muscle interferes with contractile performance. Since digitalis glycosides bind to the Na+,K+-pump, the muscles constitute a large distribution volume for these agents and are therefore an important determinant for their plasma level. 4. In cardiac insufficiency, the decrease in the concentration of Na+, K+-pumps in the myocardium is over a wide range correlated to the concomitant reduction in ejection fraction. The regulatory and pathophysiological changes in the activity and concentration of Na+, K+-pumps are important for the contractile function of skeletal muscle and heart as well as for K+ homoeostasis and the response to digitalization.

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Ouabain Binding in the Human Brain

Cited by 30 publications

References 27 publications

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Functional Brain Imaging in the Resting State and during Activation in Alzheimer's Disease: Implications for Disease Mechanisms Involving Oxidative Phosphorylation

Clinical and therapeutic significance of the Na+,K+ pump*

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