The digitalis-like steroid hormones: New mechanisms of action and biological significance

Nesher, Maoz; Shpolansky, Uri; Rosen, Haim; Lichtstein, David

doi:10.1016/j.lfs.2007.03.013

Cited by 144 publications

(117 citation statements)

References 197 publications

(226 reference statements)

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“…Future investigation of the particular β (1-3) and FXYD (1-7) subunits coexpressed with the NKAα1 and NKAα3 will identify the additional molecular players involved in tailoring the NKAα transport properties at each of these synapses. Ultimately, clarifying the molecular components and neuronal contribution of the NKA in the cochlea will suggest ways in which its activity may be altered by exogenous inhibitors as a possible means to treat hearing loss (Aperia 2007) and also, very excitingly, by naturally occurring, endogenously expressed inhibitors (Nesher et al 2007;Schoner and Scheiner-Bobis 2007) that may contribute to both normal and pathological hearing states.…”

Section: Discussionmentioning

confidence: 99%

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

McLean

Smith

Glowatzki

et al. 2008

JARO

107

105

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Processing of sound in the cochlea involves both afferent and efferent innervation. The Na,K-ATPase (NKA) is essential for cells that maintain hyperpolarized membrane potentials and sodium and potassium concentration gradients. Heterogeneity of NKA subunit expression is one mechanism that tailors physiology to particular cellular demands. Therefore, to provide insight into molecular differences that distinguish the various innervation pathways in the cochlea, we performed a variety of double labeling experiments with antibodies against three of the α isoforms of the NKA (NKAα1-3) and markers identifying particular subsets of neurons or supporting cells in whole mount preparations of the organ of Corti and spiral ganglion. We found that the NKAα3 is abundantly expressed within the membranes of the spiral ganglion somata, the type I afferent terminals contacting the inner hair cells, and the medial efferent terminals contacting the outer hair cells. We also found expression of the NKAα1 in the supporting cells that neighbor the inner hair cells and express the glutamate transporter GLAST. These findings suggest that both the NKAα1 and NKAα3 are poised to play an essential role in the regulation of the type I afferent synapses, the medial efferent synapses, and also glutamate transport from the afferent-inner hair cell synapse.

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Section: Discussionmentioning

confidence: 99%

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

McLean

Smith

Glowatzki

et al. 2008

JARO

107

105

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show abstract

“…18,19 These issues, particularly the last, have been reviewed in a series of excellent papers. [16][17][18][19][20][21][22][23] The main purpose of the present Review is to emphasize the roles of endogenous cardiotonic steroids in human health and disease-in particular with regard to the renal and cardiovascular systems-and to highlight potential therapeutic targets that have arisen as a result of research in this area. In short, we hope to establish that endogenous cardiotonic steroids have begun their journey from bench to bedside.…”

Section: Introductionmentioning

confidence: 99%

Endogenous digitalis: pathophysiologic roles and therapeutic applications

2008

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SUMMARYEndogenous digitalis-like factors, also called cardiotonic steroids, have been thought for nearly half a century to have important roles in health and disease. The endogenous cardiotonic steroids ouabain and marinobufagenin have been identified in humans, and an effector mechanism has been delineated by which these hormones signal through the sodium/potassium-transporting ATPase. These findings have increased interest in this field substantially. Although cardiotonic steroids were first considered important in the regulation of renal sodium transport and arterial pressure, subsequent work has implicated these hormones in the control of cell growth, apoptosis and fibrosis, among other processes. This Review focuses on the role of endogenous cardiotonic steroids in the pathophysiology of essential hypertension, congestive heart failure, end-stage renal disease and pre-eclampsia. We also discuss potential therapeutic strategies that have emerged as a result of the increased understanding of the regulation and actions of cardiotonic steroids.

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“…To some extent they may generally share with sterols a role in the maintenance of cell membrane structure (Pegel 1997). Due to the hydrophilicity of the glucose moiety, these molecules may have surfaceactive binding sites and properties (Folmer 2003), similar to better-known phytosterol glucosides such as ouabain and digitalin (Nesher et al 2007). For most phytosterol glucosides binding sites have not been identified.…”

Section: Introductionmentioning

confidence: 99%

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

Tabata

Wilson

et al. 2008

Neuromol Med

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Epidemiological studies of the Guamanian variants of amyotrophic lateral sclerosis (ALS) and parkinsonism, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), have shown a positive correlation between consumption of washed cycad seed flour and disease occurrence. Previous in vivo studies by our group have shown that the same seed flour induces ALS and PDC phenotypes in out bred adult male mice. In vitro studies using isolated cycad compounds have also demonstrated that several of these are neurotoxic, specifically, a number of water insoluble phytosterol glucosides of which β-sitosterol β-D-glucoside (BSSG) forms the largest fraction. BSSG is neurotoxic to motor neurons and other neuronal populations in culture. The present study shows that an in vitro hybrid motor neuron (NSC-34) culture treated with BSSG undergoes a dose-dependent cell loss. Surviving cells show increased expression of HSP70, decreased cytosolic heavy neurofilament expression, and have various morphological abnormalities. CD-1 mice fed mouse NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript chow pellets containing BSSG for 15 weeks showed motor deficits and motor neuron loss in the lumbar and thoracic spinal cord, along with decreased glutamate transporter labelling, and increased glial fibrillary acid protein reactivity. Other pathological outcomes included increased caspase-3 labelling in the striatum and decreased tyrosine-hydroxylase labelling in the striatum and substantia nigra. C57BL/6 mice fed BSSG-treated pellets for 10 weeks exhibited progressive loss of motor neurons in the lumbar spinal cord that continued to worsen even after the BSSG exposure ended. These results provide further support implicating sterol glucosides as one potential causal factor in the motor neuron pathology previously associated with cycad consumption and ALS-PDC.

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The digitalis-like steroid hormones: New mechanisms of action and biological significance

Cited by 144 publications

References 197 publications

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

Endogenous digitalis: pathophysiologic roles and therapeutic applications

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

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