title: 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.affiliation: Department of Anatomy, College of Medicine, Howard University, Washington, DC, United States of America.
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of Anatomy, College of Medicine, Howard University, Washington, DC, United States of America.
authors.forename: Liqin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Anatomy, College of Medicine, Howard University, Washington, DC, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Heinbockel
mesh_terms: D000664:Amphibian Venoms / Q000737:chemistry; D000818:Animals; D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002316:Cardiotonic Agents / Q000494:pharmacology; D002490:Central Nervous System / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008810:Mice, Inbred C57BL; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009830:Olfactory Bulb / Q000166:cytology; D010042:Ouabain / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000664:Amphibian Venoms; D002018:Bufanolides; D002316:Cardiotonic Agents; D062551:NAV1.2 Voltage-Gated Sodium Channel; C095591:chan su; C005734:bufogenin; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; C002471:cinobufagin