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Resibufogenin and cinobufagin activate central neurons through an ouabain-like action.
- Source :
-
PloS one [PLoS One] 2014 Nov 24; Vol. 9 (11), pp. e113272. Date of Electronic Publication: 2014 Nov 24 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Cinobufagin and resibufogenin are two major effective bufadienolides of Chan su (toad venom), which is a Chinese medicine obtained from the skin venom gland of toads and is used as a cardiotonic and central nervous system (CNS) respiratory agent, an analgesic and anesthetic, and as a remedy for ulcers. Many clinical cases showed that Chan su has severe side-effects on the CNS, causing shortness of breath, breathlessness, seizure, coma and cardiac arrhythmia. We used whole-cell recordings from brain slices to determine the effects of bufadienolides on excitability of a principal neuron in main olfactory bulb (MOB), mitral cells (MCs), and the cellular mechanism underlying the excitation. At higher concentrations, cinobufagin and resibufogenin induced irreversible over-excitation of MCs indicating a toxic effect. At lower concentrations, they concentration-dependently increased spontaneous firing rate, depolarized the membrane potential of MCs, and elicited inward currents. The excitatory effects were due to a direct action on MCs rather than an indirect phasic action. Bufadienolides and ouabain had similar effects on firing of MCs which suggested that bufadienolides activated neuron through a ouabain-like effect, most likely by inhibiting Na+/K+-ATPase. The direct action of bufadienolide on brain Na+ channels was tested by recordings from stably Nav1.2-transfected cells. Bufadienolides failed to make significant changes of the main properties of Nav1.2 channels in current amplitude, current-voltage (I-V) relationships, activation and inactivation. Our results suggest that inhibition of Na+/K+-ATPase may be involved in both the pharmacological and toxic effects of bufadienolide-evoked CNS excitation.
- Subjects :
- Amphibian Venoms chemistry
Animals
Bufanolides chemistry
CHO Cells
Cardiotonic Agents pharmacology
Central Nervous System cytology
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Ion Channel Gating drug effects
Ion Channel Gating genetics
Ion Channel Gating physiology
Membrane Potentials drug effects
Mice, Inbred C57BL
NAV1.2 Voltage-Gated Sodium Channel genetics
NAV1.2 Voltage-Gated Sodium Channel metabolism
NAV1.2 Voltage-Gated Sodium Channel physiology
Neurons metabolism
Olfactory Bulb cytology
Ouabain pharmacology
Patch-Clamp Techniques
Sodium-Potassium-Exchanging ATPase antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase metabolism
Bufanolides pharmacology
Neurons physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25420080
- Full Text :
- https://doi.org/10.1371/journal.pone.0113272