Neuroleptic Properties of the Ion‐Channel‐Forming Peptaibol Zervamicin: Locomotor Activity and Behavioral Effects

Abstract

Zervamicins IIA and IIB are members of the peptaibol family of peptide antibiotics. They are produced by the fungus Emericellopsis salmosynnemata. Peptaibols are known to be of potential usefulness for chemotherapeutic applications, as are other secondary fungal metabolites. Previously, we have found zervamicins to decrease spontaneous locomotor activity in mice, suggesting their neurotropic properties on an equal footing with antimicrobial activity. The current study deals with behavioral effects of zervamicins IIA and IIB in mice. According to our results, both zervamicins induce a reliable decrease in locomotion and exploratory activity measured in the hole-board test. The behavioral effects of zervamicin IIA become apparent at lower dosages (0.05-2.0 mg/kg) as compared with zervamicin IIB (0.5-12.0 mg/kg). The experiments on behavioral effects in the elevated plus maze test showed that both zervamicins caused a reliable decrease in the number of head-dippings, open-arm entries, and rearings. The observed behavioral effects may be rather associated with a decrease in the exploratory activity than with anxiety-related responses in mice. Zervamicins induced depression-like behavior of experimental animals in the forced-swim test. Both peptaibols reduce physical endurance and change motor coordination of experimental animals in the bar-holding test. Taken together, the data obtained clearly indicate that both zervamicins possess neuroleptic activity.

Membrane Permeabilization of a Mammalian Neuroendocrine Cell Type (PC12) by the Channel‐Forming Peptides Zervamicin, Alamethicin, and Gramicidin

“…Another peptaibol, ampullosporin A, was found to induce hypothermia in mice, suggesting a neuroleptic type of activity [15] [16]. Recently, for ZER neuroleptic effects and a decreased spontaneous locomotor activity were observed in behavioral studies with mice after intraperitoneal administration of 0.05 -2.0 mg/kg [17]. However, administration of 8 and 12 mg/kg caused the death of 30 and 50% of the animals, respectively, within 6 -8 h. Tritium-labelling studies showed a concentration of ca.…”

“…-It is of interest to compare the measured electrophysiological effects of the peptaibols ALA and ZER on the membrane of mammalian neuron-like cells in the concentration range of 1 -10 mm with effects reported by others on various other cell functions. These concentrations had stimulatory effects on adrenal chromaffin cell functions in in vitro studies (catechoamine release [10] and calcium entry [13]) and may be relevant for pharmacological studies of neurotropic effects of peptaibols on mammalian behavior [15] [17]. For example, upon intraperitoneal administration of 4 mg ZER/kg, the maximum safe dosage to show neurotropic effects in mice [17], the concentration of ZER in the brain was found to be 0.1 mm [18], thus much lower than the cell-damaging doses found in our patch-clamp recordings.…”

“…These concentrations had stimulatory effects on adrenal chromaffin cell functions in in vitro studies (catechoamine release [10] and calcium entry [13]) and may be relevant for pharmacological studies of neurotropic effects of peptaibols on mammalian behavior [15] [17]. For example, upon intraperitoneal administration of 4 mg ZER/kg, the maximum safe dosage to show neurotropic effects in mice [17], the concentration of ZER in the brain was found to be 0.1 mm [18], thus much lower than the cell-damaging doses found in our patch-clamp recordings. The following EC 50 (50% effective concentration) values were previously reported for ALA and ZER in permeabilization and lysis studies with procaryotic and eukaryotic cells: EC 50 ¼ 16 -30 mm (ALA, red blood cells and chromaffin cells) [9] [10], EC 50 % 50 mm (ALA, leukocytes) [11], EC 50 % 2.4 mm (ALA, insect cells) [14], EC 50 ¼ 3 mm (ZER, Gram-positive bacteria) [8].…”

Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader–Willi syndrome

“…For cell-attached voltage-clamp recording, spontaneous AP recordings were made at 29°C-31°C. The pipette solution was replaced by normal ACSF (24,25). During the electrophysiological recordings, 5 mM kynurenic acid (Sigma, St Louis, MO, USA) and 0.1 mM picrotoxin (Sigma, St Louis, MO, USA) were added in bathing ACSF to block glutamatergic and GABAergic synaptic transmission.…”

Metabolomic-Guided Isolation of Bioactive Natural Products from Curvularia sp., an Endophytic Fungus of Terminalia laxiflora

“…N-acetyl amino acids are very useful in the pharmaceutical and food industries as they play an important role in methylation, sulfuration, detoxication and antioxidation [39]. The related natural product N-acetyl-L-phenylalanyl-L-phenylalaninol has been previously isolated from culture filtrates of the fungus Emericellopsis salmosynnemata [40], a producer of the peptide antibiotic zervamicin [41,42]. The hydroxylated methylene unit found in N-acetyl-L-phenylalanyl-L-phenylalaninol was instead substituted by a carboxylic acid moiety in compound 2.…”