Anxiolytic, Analgesic and Anti-Inflammatory Effects of Peptides Hmg 1b-2 and Hmg 1b-4 from the Sea Anemone Heteractis magnifica

Abstract

Acid-sensing ion channels (ASICs) have been known as sensors of a local pH change within both physiological and pathological conditions. ASIC-targeting peptide toxins could be potent molecular tools for ASIC-manipulating in vitro, and for pathology treatment in animal test studies. Two sea anemone toxins, native Hmg 1b-2 and recombinant Hmg 1b-4, both related to APETx-like peptides, inhibited the transient current component of human ASIC3-Δ20 expressed in Xenopus laevis oocytes, but only Hmg 1b-2 inhibited the rat ASIC3 transient current. The Hmg 1b-4 action on rASIC3 as a potentiator was confirmed once again. Both peptides are non-toxic molecules for rodents. In open field and elevated plus maze tests, Hmg 1b-2 had more of an excitatory effect and Hmg 1b-4 had more of an anxiolytic effect on mouse behavior. The analgesic activity of peptides was similar and comparable to diclofenac activity in an acid-induced muscle pain model. In models of acute local inflammation induced by λ-carrageenan or complete Freund’s adjuvant, Hmg 1b-4 had more pronounced and statistically significant anti-inflammatory effects than Hmg 1b-2. It exceeded the effect of diclofenac and, at a dose of 0.1 mg/kg, reduced the volume of the paw almost to the initial volume. Our data highlight the importance of a comprehensive study of novel ASIC-targeting ligands, and in particular, peptide toxins, and present the slightly different biological activity of the two similar toxins.

Fifty Years of Animal Toxin Research at the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

“…Particular interest was shown in two homologous peptides, Hmg 1b-2 and Hmg 1b-4: both molecules have analgesic activity, similarly to diclofenac in the model of acid-induced muscle pain and acute local inflammation. However, Hmg 1b-4’s analgesic effect was more pronounced and statistically significant; in addition, this compound showed an anxiolytic effect on mouse mice behavior in the open field test [ 136 ]. The Hmg 1b-2 and Hmg 1b-4 (originally named Hcr 1b-4) peptides differed in their selectivity to ion channels: the second one has been found to be a potentiator of ASIC3 and inhibitor of ASIC1a at similar concentrations—EC 50 1.53 ± 0.07 μM and IC 50 1.25 ± 0.04 μM [ 137 ].…”

“…Thus, inhibitors of such important ion channels as TRPV1 [ 140 , 141 ], TRPA1 [ 142 , 143 ], and ASICs [ 137 , 138 , 144 ] were discovered at IBCh. Some of the found peptides potently inhibit the mammalian nociceptive sensors, produce analgesia in animal models [ 136 , 145 , 146 ], and may pave the way to novel pain killers.…”