Erythrina mulungu Alkaloids Are Potent Inhibitors of Neuronal Nicotinic Receptor Currents in Mammalian Cells

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.

Gas‐phase dissociation study of erythrinian alkaloids by electrospray ionization mass spectrometry and computational methods

“…In addition, Garín‐Aguilar and coworkers have demonstrated that inhibition of the α4β2 nicotinic receptor in the dorsal hippocampus by erysodine might be related to memory functions . The same effect has been observed for erythravine and 11‐α‐hydroxyerythravine …”

“…The bark of these species has also been employed to treat disorders of the nervous system such as insomnia, depression and epilepsy . These applications agree with the biological action reported for isolated erythrinian alkaloids and have led to the launch of several products into the pharmaceutical market. However, only a few studies about the absorption, distribution, metabolism and elimination (ADME) of these alkaloids have been published.…”

The genus Erythrina L.: A review on its alkaloids, preclinical, and clinical studies

“…Therefore, some research papers studied the possible mechanisms involved. In summary, Erythrina alkaloids are known to activate GABA A receptors (Carvalho et al, ) and are selective competitive inhibitors of nicotinic acetylcholine receptors (nAChRs; Decker et al, ), especially the α4β2 subtype (Iturriaga‐Vásquez et al, ; Setti‐Perdigao et al, ).…”

“…11α‐Hydroxyerysotrine ( 6 ), 11α‐hydroxyerythravine ( 7 ), and erythravine ( 29 ) had its CNS effects evaluated (Setti‐Perdigao et al, ). The results indicated that these alkaloids produce behavioral effects through inhibition of CNS nAChRs, particularly the α4β2 subtype.…”

Caracterização dos alcaloides de Erythrina verna

“…Os alcaloides (+)-eritravina e (+)-11-α-hidroxieritravina também mostraram inibição de receptores nicotínicos de acetilcolina no SNC que podem estar relacionados a efeitos ansiogênicos em ratos (SETTI-PERDIGÃO et al, 2013).…”