Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice

Abstract

N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca2+ dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression. The objective of the present study was to determine the antidepressant effects of either a single dose of hyperforin or lanicemine vs. their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological, and radioligand binding assays) was employed. Combined administration of hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naïve and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit, and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by hyperforin. Moreover, compound such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets.

Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia

“…As proposed by Singer et al, the increase in Na + concentration resulting from TRPC6 activation by hyperforin might inhibit serotonin reuptake via the serotonin/Na + symporter, which, together with increased synaptic plasticity, could explain the antidepressant-like activity of H. perforatum-based drugs [129]. Confirming this hypothesis, larixyl acetate, a selective blocker of TRPC6, abolishes the antidepressant-like effects of hyperforin observed in mice in the tail suspension test [130].…”

Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials

“…Hyperforin has also been demonstrated to promote post-stroke neurovascular regeneration and functional recovery via astrocytic IL-6-mediated negative immune regulation (Yao et al 2019 ) and improve post-stroke social isolation‑induced exaggeration of post‑stroke depression and post‑stroke anxiety via TGF-β (Zhang et al 2019 ). Additionally, hypericum extracts have been reported to have a protective effect on the brain, improve anxiety-like behavior (Sevastre-Berghian et al 2018 ) and exhibit an antidepressant-like activity in mice (Pochwat et al 2018 ). Besides, as a specific activator for TRPC6, hyperforin usage could reduce the growth and viability of the various human and rat cancer cell lines by apoptosis with IC 50 between 3 and 15 μM (Schempp et al 2002 ; Chen et al 2018 ; Liu et al 2019 ).…”

Biological Activity of Hypericum Perforatum L. (Hypericaceae): A Review

“…Несмотря на популярность препаратов зверобоя в качестве «мягких» антидепрессантов, механизм их действия еще не вполне изучен. Согласно современным представлениям, в число наиболее активных компонентов растения входят нафтодиантрон гиперицин, производные флороглюцина гиперфорин и адгиперфорин, бифлавоноид аментофлавон и другие флавоноиды [6][7][8][9][10][11][12][13].…”

“…Гиперфорин также уменьшал выраженность когнитивных нарушений, вызванных дизоцилпином -NMDA-антагонистом c выраженными диссоциативными и психотомиметическими свойствами. При этом in vitro гиперфорин в концентрациях 0.3-10 μМ не оказывал влияния на электрическую активность NMDA-рецепторов [13].…”