Review Article

Aconitine poisoning and its effects on various systems - A review S. Shreya, Dhanraj Ganapathy

ABSTRACT

Aconitine is a major bioactive alkaloid which is extracted from monkshood (Aconitum napellus), a plant getting its name for its blue- to purple-colored flowers, that resembles a Monk’s hood. Aconitine belongs to the Aconitum genus of Ranunculaceae family and is frequently employed in herbal medicines for its anti-inflammatory, analgesic, antirheumatic, and cardiotonic actions. Other names of Aconitine are aconite, monkshood, women’s bane, devil’s helmet, queen of poisons, and blue rocket. It has anti-inflammatory and analgesic properties. Although it has pharmacological values, it can also induce severe arrhythmia and neurotoxicity. This kind of poisoning is called as aconite poisoning. Aconitine poisoning accidents caused by misuse of herb, suicide, or homicide have been reported in recent years as one cause for fatal death. This study reveals more on the herb and its toxic nature. Along with the above, the review also aims to provide some convincing evidence for forensic experts to identify the unexplained death with postmortem examination since it cannot be detected through clinical and pathological studies. KEY WORDS: Aconitine, Poisoning, Herbal, Neurotoxicity

INTRODUCTION human pancreatic cancer, indicating that aconitine may serve as a potent therapeutic strategy for the treatment Herbal medicines are commonly used as alternative of several cancers.[6] However, the application of medicines in Asian countries, more in China, to treat aconitine has been limited in clinical practice due to various diseases due to its natural, harmless, and less its toxic effects on the heart and nervous system. adverse effects for thousands of years. Aconitum plants have been extensively applied to treat multiple diseases To further clarify the potential risk of aconitine, the in China and some other Asian countries. Traditional widespread application of toxicological characteristics Chinese medicines are processed by soaking or and pharmacokinetics is reviewed.[7] Moreover, boiling before consumption to reduce the toxicity.[3,4] gastrointestinal, neurological, and cardiovascular In general, herbal poisoning may frequently occur due symptoms were observed regularly in aconitine to inadequate processing and preparation, overdose, poisoning cases. contamination, misidentification, and even in some suicidal or homicidal cases. However, it is difficult for ACONITINE DOSAGING forensic experts to find the specific results in present With the increasing popularity of herbal drugs, forensic autopsy of aconitine-induced death.[1,2,5] herb-induced fatal poisoning cases have frequently Previous studies on Aconitum plants have shown its happened as a result of inappropriate use of herbs pharmacological properties such as anti-inflammation, in recent years. Aconitine, one of the abundant and high bioactive diterpenoid alkaloids, has a narrow analgesia, and antirheumatism. In addition, aconitine therapeutic index, and it also brings great challenges could also suppress tumor growth and induce cell to understand its appropriate dosage.[8,9] apoptosis by nuclear factor-κB signaling pathway in Previous studies revealed the half-maximally lethal

Access this article online dose (LD50) aconitine for mice is 1.8 mg/kg by oral administration, and the minimum lethal dose of oral Website: jprsolutions.info ISSN: 0975-7619 administration in humans is evaluated to be 1–2 mg.[10]

Department of Prosthodontics, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India

*Corresponding author: Dhanraj Ganapathy, Department of Prosthodontics, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai – 600 077, Tamil Nadu, India. E-mail: [email protected]

Received on: 14-08-2018; Revised on: 19-09-2018; Accepted on: 27-10-2018

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Monoester-diterpenoid alkaloids are considered as aconine and aconine derivatives. Considering that hydrolyzed products of diester diterpenoid alkaloids the therapeutic dose and the toxic dose of aconitine

(DDAs). Previous studies has discussed the LD50 are close, it is crucial to use safely as a medicine in of aconitine for mice by intravenous injection clinical applications. Indeed, the establishment of the is approximately 38 times of its hydrolysates.[11] pharmacokinetic parameters of aconitine would be Symptoms of aconitine poisoning frequently appear essential to make it play better pharmacological effects within 2 h or even several minutes through oral in clinics.[18,19] Cytochrome P450 (CYP450) enzymes, ingestion, indicating that it can be easily absorbed belonging to membrane-bound hemoproteins, are with oral administration. It has been demonstrated involved in approximately 80% of phase I metabolism that aconitine can also be absorbed into systemic of drugs and play important roles in the oxidative circulation through the human skin, leading to fatal metabolism of drugs and exogenous substances. and non-fatal poisoning. However, there is no specific CYP3A has been found to be the dominant CYP450 antidote and the current treatment is mainly based expressed in both the liver and intestine, and it on the supporting therapies. Nevertheless, it was principally catalyzes phase I metabolism of various reported that there were some effective treatment alkaloids in human intestine and liver microsomes. methods or medicines to improve cardiac arrhythmias Whether CYP450 enzymes are involved in aconitine in aconitine-induced poisoning accidents including metabolism has also been further investigated. It has charcoal hemoperfusion, amiodarone, magnesium, been reported that aconitine is mainly metabolized by and lidocaine.[12,13] On the one hand, aconitine is very CYP3A and CYP1A1/2 into less toxicity derivatives unstable and decomposed easily in the human body. in rat liver microsomes.[20] It is not detected routinely for common toxicology analysis in present forensic practice. Meanwhile, little It should be noted that the detection of aconitine attention is paid to aconitine poisoning in current concentrations in body fluids plays a vital role in clinic clinical practice and medicolegal expertise. and forensic toxicology analysis of suspected poisoning incidents. As aconitine can decompose or metabolize ACONITINE TOXICOLOGY rapidly, it is also difficult to detect aconitine contents in human body fluids. In previous studies, some methods It is rather difficult to define precisely the have been employed for detecting aconitine such as therapeutic dose and toxic dose of aconitine due to capillary electrophoresis, gas chromatography–mass its narrow therapeutic index. The cardiotoxicity and spectrometry (MS), and high-performance liquid neurotoxicity caused by inadequate consumption of chromatography (LC).[21,22] However, low selectivity aconitine have been occasionally reported in recent and sensitivity have restricted the application of these years.[14] It has been reported that aconitine can reach methods to some extent. At present, LC tandem MS relatively high concentrations in the liver, kidney, has developed a valid and precise method to analyze and heart following by oral intake of aconitine. aconitine contents in blood and urine samples. Taking Patients with aconitine poisoning generally present into account that aconitine is metabolized fast into with a series of gastrointestinal, cardiovascular, and several derivatives in animal and human models, neurologic symptoms. The gastrointestinal features accordingly, the findings of aconitine and primary can be nausea, vomiting, diarrhea, and abdominal metabolites in blood, urine, or herb medicine samples pain. Neurologic symptoms include numbness in together with the important clinical manifestations mouth and limbs, paraesthesia, central nervous will provide some indispensable evidence of aconitine system depression, respiratory muscle depression, poisoning in present forensic practice.[23] convulsions, and seizures.[15,16] Cardiovascular manifestations predominantly include hypotension, SYMPTOMS OF ACONITINE palpitations, chest pain, bradycardia, sinus tachycardia, POISONING ventricular tachycardia, and ventricular fibrillation. Symptoms of aconitine poisoning and pathological DETERMINATION OF ACONITINE changes in postmortem examination of aconitine, POISONING which has a narrow therapeutic window, are considered to be the principal highly toxic DDA in aconitum The ester groups combining with C8 and C14 are alkaloids.[24] The incubation period between ingestion considered to be primarily responsible for the high of aconitine and the onset of symptoms may be as toxicity of aconitine, while hydrolysis of esters can short as several minutes, indicating that aconitine can reduce its toxicity dramatically.[17] Aconitine is not be absorbed rapidly after oral administration by the only well known for its pharmacology actions but upper gastrointestinal tract. Furthermore, the severity also recognized as a toxic ingredient that needs to of symptoms appears to be related to the doses and be processed properly to use it safely for humans. time of exposure of aconitine. In particular, aconitine Aconitine can be hydrolyzed to less toxic benzyl is also quickly decomposed or eliminated with a

678 Drug Invention Today | Vol 11 • Issue 3 • 2019 S. Shreya and Dhanraj Ganapathy short half-life.[25] The signs of asphyxia are observed in aconitine-treated cardiomyocytes.[34] Calcium at autopsy including facial and nail bed cyanosis. regulatory proteins, including Na+–Ca2+ exchange Foamy liquid can be seen in the endotracheal cavity. (NCX1), ryanodine receptor (RyR2), dihydropyridine The postmortem examination may find hemorrhagic receptor (DHPR), and sarco-endoplasmic reticulum points distributed on the surface of the heart and (SR) Ca(2+)-ATPase2 in sarcoplasmic reticulum, lungs.[26] Moreover, the microscopic examination are capable of maintaining intracellular calcium has been reported to reveal bilateral intrapulmonary homeostasis in myocardial cells. Previous publications hemorrhage and edema, congestion of multiple organs, have described that aconitine could damage myocardial and bilateral pleural effusions in different degree. cells, increase the expression of RyR2, and decrease It is necessary for forensic pathologists to exclude the expression of NCX1 and DHPR-a1 significantly, the presence of fatal diseases and physical injuries. thus leading to the unbalance of intracellular calcium Meanwhile, the results of toxicological analysis homeostasis.[35] The results of current research showed that aconitine and its derivatives were positive provided strong evidence that aconitine-induced and other toxic substances and illegal drugs were arrhythmia was associated with intracellular Ca2+ negative in blood, gastric content, or urine samples signals and pre-treatment with aconitine reduced the of victims. In this situation, death was generally sarcoplasmic reticulum Ca2+-ATPase expression and considered to be caused by aconitine poisoning.[27,28] increased the expression of Na+/Ca2+ exchange in rat ventricular myocytes, which is consistent with the EFFECT OF ACONITINE ON THE previous studies.[36,37] CARDIAC SYSTEM Connexin43 (Cx43) is the principal gap junction Previous studies have revealed that aconitine could protein in the heart. Previous studies have demonstrated induce various types of life-threatening arrhythmias that Ser368, a protein kinase C site, is involved in the causing variations in heart rate such as bradycardia, regulation of gap junction function. It is well known nodal tachycardia, cardiac fibrillation, bidirectional that the Ser368 remains phosphorylation status ventricular tachycardia, and intraventricular under normal circumstances. Aconitine could induce block. Aconitine induced suppression of systemic Cx43 and protein kinase C-a dephosphorylation and lupus erythematosus and attenuate the pathologic alter Ca2+ oscillation frequency, which probably is impairment was confirmed by vivo experiment using associated with cellular signal transduction, finally murine model. Aconitine-induced arrhythmias were leading to cardiac toxicity in cultured neonatal rats observed in the isolated atrium of rabbit, and the cardiomyocytes.[8] results showed that aconitine might directly stimulate sinus node and inhibit the propagation of impulses More importantly, aconitine could also shorten action in some degree.[29] Emerging evidence indicated that potential duration and reduce L-type calcium currents, aconitine could block the inactivation of voltage- thereby contributing to the proarrhythmic effects dependent sodium channels at the resting membrane in human-induced pluripotent stem cell-derived potential causing sustained Na+ influx, therefore cardiomyocytes. The effects of aconitine-caused leading to arrhythmia. The aconitine-induced blockade arrhythmia and underlying mechanisms were further of HERG and Kv1.5 in Xenopus laevis oocytes is studied in human cardiomyocytes model. In addition, considered to be one of the mechanisms of cardiac it is noteworthy that the NCX system plays a vital arrhythmias.[30,31] Moreover, in H9c2 cells and cultured role in regulating cardiac contractility and electrical neonatal rat cardiomyocytes, aconitine could produce activity in different animal modes.[38] KB-R9743 the inhibition effect on ultrarapid delayed rectifier K+ (KBR), a selective inhibitor of NCX in cardiac muscle, current in a time- and dose-dependent manner.[32] is capable of inhibiting aconitine-4. Gao et al. induced arrhythmias in guinea pigs and isolated ventricular Ca2+ is one of the most important secondary myocytes. messengers which plays crucial roles in the process of cell signal transduction and electrical activity Drug–DNA interaction is regarded as one of the of myocardial cells. Meanwhile, disruption of the reasons of the DNA damage of some drugs. The intracellular Ca2+ homeostasis is an important cytotoxicities of aconitine were further investigated mechanism of arrhythmic toxicity of aconitine.[33] It in rat myocardial cell H9c2.[39] The results showed is well known that aconitine can induce abnormalities that aconitine could exhibit cytotoxic activities of spontaneous beating rate, amplitude of spontaneous including promotion of the apoptotic rate, inhibition oscillations, and intracellular Ca2+ signals and of the growth of myocardial cells, and interaction increase the relative intracellular Ca2+ concentration with DNA by intercalation and electrostatic binding, in cultured primary cardiomyocytes, indicating implying that the aconitine-induced cardiac toxicity that disruption of intracellular Ca2+ homeostasis and DNA injury are correlated in a certain degree. Our generally contributes to the arrhythmic toxicity study showed that aconitine could induce apoptosis

Drug Invention Today | Vol 11 • Issue 3 • 2019 679 S. Shreya and Dhanraj Ganapathy of H9c2 cells at least in part through mitochondria- in China and some Asian countries for the treatment dependent apoptotic pathway.[40] However, the specific of various common medical problems such as pains, mechanism remains unknown and still needs further rheumatoid arthritis, and cardiac disorders. Aconitum study. alkaloids, mainly containing aconitine, hypaconitine, and mesaconitine, are important representatives EFFECT OF ACONITINE ON THE derived from the roots of plants in Aconitum genus.[43] NEURAL SYSTEM Aconitine, a high bioactive diterpenoid alkaloid derived from Aconitum plants, not only has great medicinal The neurotoxic effects of aconitine have been value but also can cause serious poisonous effects researched in different cell types. It was reported that which cannot be detected through clinical and aconitine could block neuromuscular transmission and pathological studies in a postmortem records. cause depolarization in mice and frog skeletal muscles. Despite this, based on the accumulation of traditional More importantly, aconitine was reported to decrease processing experiences and new techniques, aconitine the amplitude and block end-plate potentials and nerve can also be adequately processed to reduce its toxic action potentials, which contribute to neuromuscular effects and play better pharmacological effects. In our blockade accompanied by excessive presynaptic present review, we describe the toxicological effects depolarization in the rat isolated phrenic nerve- of aconitine and further analyze aconitine poisoning diaphragm muscles of rats.[41] Interestingly, a piece cases in forensic practice. 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