Dopaminergic Neurotoxicity of Cyanide: Neurochemical, Histological, and Behavioral Characterization

doi:10.1006/taap.1994.1102

Toxicology and Applied Pharmacology

Volume 126, Issue 1, May 1994, Pages 156-163

https://doi.org/10.1006/taap.1994.1102 Get rights and content

Abstract

Previous reports have shown that dopamine (DA) is depleted in the brains of animals treated with cyanide. To develop a model for studying the mechanisms of cyanide-induced changes in dopaminergic systems, mice were treated with cyanide (KCN, 6 mg/kg, sc) twice a day for 7 days and 16 hr after the last dose neurochemical, histological, or behavioral parameters were evaluated. DA levels in KCN-treated animals decreased in the striatum (41%), hippocampus (30%), and cerebral cortex (13%) as compared to saline-treated controls. In striatal and hippocampal tissues, but not in cerebral cortex, malondialdehyde levels increased 43 and 57%, respectively, as compared to controls, indicating that peroxidation of lipids occurred in these brain areas. Over 30% of the treated mice exhibited decreased locomotor activity and akinesia, which were suppressed by ℓ-DOPA (100 mg/kg, ip). Tyrosine hydroxylase (TH) immunohistochemical examination of brains from cyanide-treated animals showed a reduced number of TH-positive cells in substania nigra, indicating a loss of dopaminergic neurons. In contrast, acute cyanide (KCN, 6 mg/kg, sc) did not produce significant neurochemical or behavioral changes. Under these treatment conditions, cyanide produces a central dopaminergic toxicity which is characterized by decreased DA levels in select brain areas, impaired locomotor activity, and neuronal damage.

References (0)

Cited by (66)

Chemical warfare agents and the nervous system
2020, Handbook of Toxicology of Chemical Warfare Agents
The use of chemicals in warfare dates back centuries, with modern chemical warfare beginning in World War I. More recent use of organophosphorus nerve agents in the Syrian civil war has highlighted the continuing worldwide concern for the misuse of chemical warfare agents (CWAs). A number of different types of CWAs can have deleterious effects on the nervous system. We briefly describe cellular function within the nervous system, factors that make the nervous system particularly sensitive to CWAs and other toxicants, and the different basic types of responses to neurotoxicants. Emphasis is placed on the acute and chronic neurological consequences of exposure to organophosphorus anticholinesterases, and both cholinergic and noncholinergic mechanisms in the expression of their toxicity and its modulation. A brief overview of the role of anticholinesterases in Gulf War illnesses is included. Additional information is provided with three other classes of CWAs, cyanides, sulfur mustard, and quinuclidinyl benzilate.
Acute cyanide toxicity and its treatment: The body is dead and may be red but does not stay red for long
2020, Handbook of Toxicology of Chemical Warfare Agents
This chapter discusses the military and paramilitary use of acute cyanide poisoning as a weapon.
Cyanide has been known as a poison since antiquity. While largely ineffective as a military weapon, cyanide has been used, with modest success, as a tool of assassination. During World War II, cyanide pesticide formulations were used extremely effectively as tools of mass murder. Cyanide is a mitochondrial toxin that impairs cellular respiration, causing morbidity or mortality within a short time. It is predominantly a neurotoxin, and its toxicity is mediated through inhibition of cytochrome oxidase, an end-chain enzyme of mitochondrial respiration. Cyanide’s actions are complex and cannot be attributed solely to deprivation of cellular oxygen. Recent mechanistic studies show that cyanide inhibits multiple enzymes and alters several vital intracellular processes that lead to a cascade of toxic events. The treatment for cyanide poisoning should be instituted immediately and aggressively. In recent times hydroxocobalamin has become the antidote of choice for acute cyanide poisoning. Supplemental oxygen therapy is also regarded as a critical part of supportive care.
Prenatal exposure to oxidative phosphorylation xenobiotics and late-onset Parkinson disease
2018, Ageing Research Reviews
Late-onset Parkinson disease is a multifactorial and multietiological disorder, age being one of the factors implicated. Genetic and/or environmental factors, such as pesticides, can also be involved.
Up to 80% of dopaminergic neurons of the substantia nigra are lost before motor features of the disorder begin to appear. In humans, these neurons are only formed a few weeks after fertilization. Therefore, prenatal exposure to pesticides or industrial chemicals during crucial steps of brain development might also alter their proliferation and differentiation.
Oxidative phosphorylation is one of the metabolic pathways sensitive to environmental toxicants and it is crucial for neuronal differentiation. Many inhibitors of this biochemical pathway, frequently found as persistent organic pollutants, affect dopaminergic neurogenesis, promote the degeneration of these neurons and increase the risk of suffering late-onset Parkinson disease.
Here, we discuss how an early, prenatal, exposure to these oxidative phosphorylation xenobiotics might trigger a late-onset, old age, Parkinson disease.
Behavioral toxicity of sodium cyanide following oral ingestion in rats: Dose-dependent onset, severity, survival, and recovery
2018, Food and Chemical Toxicology
Citation Excerpt :
A study on the role of dopamine in the neurotoxicity of cyanide (Kanthasamy et al., 1994) assessed behavioral changes in mice following 7 days of twice daily subcutaneous (SC) injections of cyanide (6.0 mg/kg KCN per injection, assessment carried out 16 h after final injection). The results showed a significant decrease in spontaneous locomotion as well as an increase in measures of akinesia and catalepsy (Kanthasamy et al., 1994). Administrations of 4.0 mg/kg NaCN intravenously (IV) to rats 4 h prior to a neurobehavioral assessment screen revealed deficits in grooming, posture, activity level, and various motoric functions in the cyanide-exposed rats (Dodds et al., 1992).
Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical reagent that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional-poisoning hazard. Thus, laboratory studies are needed to understand the dose-dependent progression of toxicity/lethality following ingestion of cyanide-poisoned foods/liquids. We developed an oral-dosing method in which a standard pipette was used to dispense a sodium cyanide solution into the cheek, and the rat then swallowed the solution. Following poisoning (4-128 mg/kg), overt toxic signs were recorded and survival was evaluated periodically up to 30 hours thereafter. Toxic signs for NaCN doses higher than 16 mg/kg progressed quickly from head burial and mastication, to lethargy, convulsions, gasping/respiratory distress, and death. In a follow-on study, trained operant-behavioral performance was assessed immediately following cyanide exposure (4-64 mg/kg) continuously for 5 h and again the following day. Onset of behavioral intoxication (i.e., behavioral suppression) occurred more rapidly and lasted longer as the NaCN dose increased. This oral-consumption method with concomitant operantbehavioral assessment allowed for accurate dosing and quantification of intoxication onset, severity, and recovery, and will also be valuable in characterizing similar outcomes following varying medical countermeasure drugs and doses.
Daily consumption of methylene blue reduces attentional deficits and dopamine reduction in a 6-OHDA model of Parkinson's disease
2017, Neuroscience
Citation Excerpt :
MB was shown to restore motor function and preserve striatal cellular function in a rotenone model of PD (Wen et al., 2011), but MB’s effects on cognitive functions in PD models are unknown. Mitochondrial dysfunction is a common property of neurodegeneration in PD patients as well as animal models of PD (Janetzky et al., 1994; Mizuno et al., 1998; Fukae et al., 2007; Subramaniam and Chesselet, 2011; Subramaniam et al., 2014), and oxidative stress is considered the primary cause of dopaminergic apoptosis in PD (Kanthsamy et al., 1994; Pallanck and Greenamyre, 2006; Schapira, 2008). Therefore, MB has the potential to be an effective neuroprotective agent by enhancing cell metabolism and reducing reactive oxidative species (Poteet et al., 2012).
Recently, alternative drug therapies for Parkinson’s disease (PD) have been investigated as there are many shortcomings of traditional dopamine-based therapies including difficulties in treating cognitive and attentional dysfunction. A promising therapeutic avenue is to target mitochondrial dysfunction and oxidative stress in PD. One option might be the use of methylene blue (MB), an antioxidant and metabolic enhancer. MB has been shown to improve cognitive function in both intact rodents and rodent disease models. Therefore, we investigated whether MB might treat attentional deficits in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). MB also has neuroprotective capabilities against neurotoxic insult, so we also assessed the ability of MB to provide neuroprotection in our PD model. The results show that MB could preserve some dopamine neurons in the substantia nigra par compacta when 6-OHDA was infused into the medial forebrain bundle. This neuroprotection did not yield a significant behavioral improvement when motor functions were measured. However, MB significantly improved attentional performance in the five-choice task designed to measure selective and sustained attention. In conclusion, MB might be useful in improving some attentional function and preserving dopaminergic cells in this model. Future work should continue to study and optimize the abilities of MB for the treatment of PD.
Cyanide Toxicity and its Treatment
2015, Handbook of Toxicology of Chemical Warfare Agents: Second Edition
Cyanide is a highly reactive nucleophile abundantly present in the environment and is regarded as a potent suicidal, homicidal, and genocidal agent. The notoriety of cyanide has been known to mankind since antiquity. Sources of industrial and dietary exposure of cyanide are many, but the most notable source of exposure is inhalation of fire smoke in industrial, residential, or other accidental fires. Cyanide is a mitochondrial toxin that impairs cellular respiration, causing morbidity or mortality within a short time. It is predominantly a neurotoxin, and its toxicity is mediated through inhibition of cytochrome oxidase, an end-chain enzyme of mitochondrial respiration. Cyanide’s actions are complex and cannot be attributed solely to deprivation of cellular oxygen. Recent mechanistic studies show that cyanide inhibits multiple enzymes and alters several vital intracellular processes that lead to a cascade of toxic events. The treatment for cyanide poisoning should be instituted immediately and aggressively. There are numerous antidotes for cyanide poisoning, but methemoglobin inducers like amyl nitrite and/or sodium nitrite in combination with a sulfur donor like sodium thiosulfate is the most common treatment strategy for cyanide intoxication. Many of the cyanide antidotes are not free from side effects; therefore, newer molecules continue to be explored for cyanide antagonism. Many mechanistic-based antidotes have been evaluated in the recent past. This chapter addresses the established concepts and recent advances in toxicology of cyanide and its treatment measures.

View all citing articles on Scopus

View full text

Regular ArticleDopaminergic Neurotoxicity of Cyanide: Neurochemical, Histological, and Behavioral Characterization

Abstract

Regular Article
Dopaminergic Neurotoxicity of Cyanide: Neurochemical, Histological, and Behavioral Characterization