Aconitine disrupts serotonin neurotransmission via 5‐hydroxytryptamine receptor in zebrafish embryo

Abstract

Medicinal plants of the genus Aconitum are one of the most commonly used herbs in traditional medicine in East Asia to treat conditions related to the heart, pain, or inflammation. However, these herbs are also dangerous as accidental poisoning due to misuse is a recurring issue. These plants contain a number of diester‐diterpenoid alkaloid compounds and aconitine is the most abundant and active one. This study investigated neurotoxicity of aconitine to zebrafish embryos in early development in relation to serotonin regulation. Experimental results showed that aconitine exposure (1, 10, and 100 μM) increased frequency of coiling behavior in zebrafish embryos in a dose‐dependent manner and this effect can be triggered by either exposure to 5‐hydroxytryptamine 1A (5‐HT1A) receptor agonist (±)‐8‐hydroxy‐2‐(dipropylamino)tetralin (8‐OH‐DPAT) or overexpression of serotonin receptor 5‐htr1ab. At the same time, coiling behavior caused by aconitine exposure could be rescued by co‐exposure to 5‐HT1A receptor antagonist WAY‐100635 Maleate (WAY100635) and knockdown of 5‐htr1ab using morpholino. Exposure to aconitine also significantly increased serotonin receptor 5‐htr1ab and 5‐htr1bd gene expression at 24 h post fertilization (hpf), but decreased their expression and protein expression of the serotonin receptor at 96 hpf with the high dose. These results suggest that neurotoxicity caused by aconitine is mediated through the 5‐HT receptor.

Dopamine Homeostasis Imbalance and Dopamine Receptors-Mediated AC/cAMP/PKA Pathway Activation are Involved in Aconitine-Induced Neurological Impairment in Zebrafish and SH-SY5Y Cells

“…In the present studies, aconitine-induced neurotoxicity possibly involves disturbance of ion homeostasis, induction of oxidative stress and apoptosis, mitochondrion injury, interference with energy metabolism, and alteration of neurotransmitter levels (Yamanaka et al, 2002;Peng et al, 2009;Zhao et al, 2010;Chen et al, 2021;Liang Yang et al, 2021). The typical clinical features of aconitine poisoning involved involuntary tremors and progressive dyskinesia (Pan and Peng, 2017).…”

“…Although the brain tissue of zebrafish is simple, their embryos develop rapidly and the nervous system has matured on 5 days postfertilization (dpf) (Schweitzer and Driever, 2009). Overall, zebrafish has emerged as a promising and ideal model to investigate the mechanisms of druginduced neurotoxicity (Chen et al, 2021). In this study, we employed zebrafish larvaes and SH-SY5Y cells to quantify the effects of aconitine on morphology, neurobehavior and cell viability.…”

Aconitum carmichaelii triggers neurotoxicity and Parkinson‐like symptoms through initiation of ROS‐mitochondrial apoptosis and the Nox5/DJ‐1 signaling pathway

“…Hao et al reported that aconitine disrupts serotonin neurotransmission via the 5-hydroxytryptamine receptor and increases the frequency of coiling behavior in a dose-dependent manner. [65] Furthermore, it has been reported that aconitine induces developmental toxicity through ROS-mediated mitochondrial apoptosis involving the Nrf2/HO-1 and JNK/Erk pathways. [66] Different from the developmental toxicity mechanisms, our study suggested A. carmichaelii induces the neurotoxicity mechanism through excessive ROS involving Nox5 and DJ-1.…”

“…Hao et al. reported that aconitine disrupts serotonin neurotransmission via the 5‐hydroxytryptamine receptor and increases the frequency of coiling behavior in a dose‐dependent manner [65] . Furthermore, it has been reported that aconitine induces developmental toxicity through ROS‐mediated mitochondrial apoptosis involving the Nrf2/HO‐1 and JNK/Erk pathways [66] .…”

Cardiotoxicity of (−)‐borneol, (+)‐borneol, and isoborneol in zebrafish embryos is associated with Na+/K+‐ATPase and Ca2+‐ATPase inhibition

“…Zebrafish embryos were exposed to three isomers of borneol from 4 hpf and were fixed by 4% paraformaldehyde overnight when the embryos developed to 72 hpf. The basic method of antibody staining is similar to our previous description (Chen et al, 2021). Zebrafish larvae sections were treated with proteinase K (Gibco, Carlsbad, USA) and rinsed with PBST (1× PBS containing 0.1% Tween20).…”