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Comparative Action of Cardiotonic Steroids on Intracellular Processes in Rat Cortical Neurons
A V Lopachev1, O M Lopacheva, K A Nikiforova
1Research Center of Neurology, Moscow, 125367, Russia.
Biochemistry. Biokhimiia
|April 6, 2018
Summary
Cardiotonic steroids (CTS) like digoxin and bufalin activate specific cell signaling pathways in rat cortical cells. Their toxic effects are linked to ERK1/2 activation and complex MAP kinase profiles, not just Na+,K+-ATPase inhibition.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Cardiotonic steroids (CTS) bind to Na+,K+-ATPase, influencing cell signaling, proliferation, and apoptosis.
- Ouabain is a well-studied CTS, but the effects of others, like digoxin and bufalin, on nervous tissue are largely unknown.
- Previous work showed ouabain activates mitogen-activated protein kinases (MAP kinases): ERK1/2, p38, and JNK.
Purpose of the Study:
- To compare the effects of digoxin and bufalin, distinct CTS subclasses, on primary rat cortical cells.
- To investigate the relationship between Na+,K+-ATPase inhibition and MAP kinase activation by different CTS.
- To elucidate the signaling cascades involved in CTS-induced toxicity in neurons.
Main Methods:
- Primary culture of rat cortical cells.
- Treatment with digoxin and bufalin at various concentrations and time points.
- Measurement of Na+,K+-ATPase inhibition.
- Analysis of MAP kinase (ERK1/2, p38, JNK) activation.
Main Results:
- CTS toxicity is not solely dependent on Na+,K+-ATPase inhibition levels.
- Digoxin and bufalin activate ERK1/2 and p38, similar to ouabain, but with different kinetics.
- Digoxin, unlike bufalin and ouabain, did not reduce JNK activation with prolonged exposure.
- ERK1/2 activation correlates directly with Na+,K+-ATPase inhibition, while other MAP kinases show complex activation patterns.
- CTS-induced MAP kinase activation occurs at concentrations inhibiting Na+,K+-ATPase containing the α1 subunit.
Conclusions:
- The toxic effects of CTS at moderate Na+,K+-ATPase inhibition levels involve ERK1/2 activation and complex MAP kinase signaling.
- Differential activation of JNK and p38 by various CTS suggests involvement of Na+,K+-ATPase interacting proteins.
- Signaling pathways activated by CTS in neurons are mediated via the α1 subunit of Na+,K+-ATPase.
- The distinct signaling profiles of CTS in neurons are influenced by their varying affinities for Na+,K+-ATPase.
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