Abstract
Crude extracts and three isolated alkaloids from Erythrina mulungu plants have shown anxiolytic effects in different animal models. We investigated whether these alkaloids could affect nicotinic acetylcholine receptors and if they are selective for different central nervous system (CNS) subtypes. Screening experiments were performed using a single concentration of the alkaloid co-applied with acetylcholine in whole cell patch-clamp recordings in three different cell models: (i) PC12 cells natively expressing α3* nicotinic acetylcholine receptors; (ii) cultured hippocampal neurons natively expressing α7* nicotinic acetylcholine receptors; and (iii) HEK 293 cells heterologoulsy expressing α4β2 nicotinic acetylcholine receptors. For all three receptors, the percent inhibition of acetylcholine-activated currents by (+)-11á-hydroxyerysotrine was the lowest, whereas (+)-erythravine and (+)-11á-hydroxyerythravine inhibited the currents to a greater extent. For the latter two substances, we obtained concentration-response curves with a pre-application protocol for the α7* and α4β2 nicotinic acetylcholine receptors. The IC50 obtained with (+)-erythravine and (+)-11á-hydroxyerythravine were 6 µM and 5 µM for the α7* receptors, and 13 nM and 4 nM for the α4β2 receptors, respectively. Our data suggest that these Erythrina alkaloids may exert their behavioral effects through inhibition of CNS nicotinic acetylcholine receptors, particularly the α4β2 subtype.
Highlights
Erythrina mulungu (Papilionaceae) is a native tree from Southern Brazil, known as mulungu or coral tree due to its reddish flowers [1]
Because the E. mulungu alkaloids are structurally related to DHbE and other erythrinian alkaloids known to act on nicotinic receptors [18], we investigated three orally active E. mulungu alkaloids (Fig. 1) as possible modulators of central nervous system (CNS) nicotinic receptor channels using patch-clamp electrophysiology
Hippocampal neurons, which predominantly express a7* nicotinic acetylcholine receptors [19,22], were stimulated by 100 mM acetylcholine and concomitantly by acetylcholine and one of the three alkaloids at 100 mM (Fig. 2A). (+)-Erythravine and (+)-11a-hydroxyerythravine reduced the peak amplitude of acetylcholine-evoked currents to 32.062.0% and 22.564.4% of control, respectively
Summary
Erythrina mulungu (Papilionaceae) is a native tree from Southern Brazil, known as mulungu or coral tree due to its reddish flowers [1]. Three previously known and one novel erythrinian alkaloid recently isolated from the flowers of E. mulungu reproduced some of the CNS effects of the polar extracts [7,8,9,10]. Oral administration of (+)-erythravine and (+)11a-hydroxyerythravine induced anxiolytic-like effects comparable to that of diazepam in mice, while (+)-11a-hydroxyerysotrine was only effective in some tests [8,9]. Because these alkaloids were effective at low oral doses (3–10 mg/kg p.o.) that did not disrupt locomotion or exploratory activity, the authors suggested that the mechanism was non-GABAergic [8], but the molecular targets remained to be investigated
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