Resibufogenin and cinobufagin activate central neurons through an ouabain-like action.

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.

• Authors: Ze-Jun Wang, Liqin Sun, Thomas Heinbockel
• Journal: PloS one (PLoS One) Vol. 9 Issue 11 Pg. e113272 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25420080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amphibian Venoms
• Bufanolides
• Cardiotonic Agents
• NAV1.2 Voltage-Gated Sodium Channel
• chan su
• bufogenin
• Ouabain
• Sodium-Potassium-Exchanging ATPase
• cinobufagin

Topics

• Amphibian Venoms (chemistry)
• Animals
• Bufanolides (chemistry, pharmacology)
• CHO Cells
• Cardiotonic Agents (pharmacology)
• Central Nervous System (cytology)
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Ion Channel Gating (drug effects, genetics, physiology)
• Membrane Potentials (drug effects)
• Mice, Inbred C57BL
• NAV1.2 Voltage-Gated Sodium Channel (genetics, metabolism, physiology)
• Neurons (metabolism, physiology)
• Olfactory Bulb (cytology)
• Ouabain (pharmacology)
• Patch-Clamp Techniques
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors, metabolism)