Effects of organophosphorous compounds on fatty acid compositions and oxidative phosphorylation system in the brain of rats

Fukushima, Tetsuhito; Hōjō, Nobumasa; Isobe, Akio; Shiwaku, Kuninori; Yamane, Yoshihiro

doi:10.1016/s0940-2993(97)80123-6

Cited by 13 publications

(4 citation statements)

References 19 publications

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“…Inhibition of COx appears to be the primary mechanism for ATP depletion. This is further supported by the findings that AChE-inhibiting OP insecticides cause inhibition of oxidative phosphorylation in the rat brain [60].…”

Section: Role Of No/nossupporting

confidence: 54%

Anticholinesterase Toxicity and Oxidative Stress

Milatović

Gupta

Aschner

2006

The Scientific World JOURNAL

261

144

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Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.

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Section: Role Of No/nossupporting

confidence: 54%

Anticholinesterase Toxicity and Oxidative Stress

Milatović

Gupta

Aschner

2006

The Scientific World JOURNAL

261

144

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“…NO appears to regulate the coupling between energy supply and demand, it increases skeletal muscle blood flow and glucose transport, and inhibits glycolysis and mitochondrial respiration (Kaminski and Andrade 2001). The findings of Fukushima et al (1997) and Gultekin et al (2000) further support the contention that the AChE-inhibiting OP insecticides cause lipid peroxidation and inhibition of oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 61%

Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity

Gupta

Milatović

Dettbarn

2002

Archives of Toxicology

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Oxidative stress, as determined by increased lipid peroxidation, has been implicated in the pathology of myotoxicity. As a model system to study the response of muscle to oxidative insults, we have studied the effects of diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity on levels of nitric oxide (NO) and energy metabolites in rat skeletal muscles. In in vivo experiments, citrulline levels as indicators of NO and NO synthase (NOS), and ATP and phosphocreatine (PCr) as indicators of mitochondrial dysfunction, were determined using HPLC methods 15 min, 30 min, 60 min, 2 h, and 24 h after intoxication. Within 15 min of DFP exposure, with onset of fasciculations, citrulline levels were significantly elevated in all three muscles [soleus, extensor digitorum longus (EDL), and diaphragm]. Maximum increases in citrulline (272-288%) were noted 60 min after DFP injection. At this time point, acetylcholinesterase activity was reduced by 90-96% (soleus < diaphragm < EDL). The levels of ATP and PCr were maximally reduced (30-43%), and total adenine nucleotides, and total creatine compounds showed declines. The findings revealed that the increase in NOS activity and NO was greater than the decrease of ATP and PCr. Since memantine (MEM) has been shown to reduce nerve and muscle hyperactivity, we have studied the possible protective effect of MEM on the DFP-induced biochemical changes. Pretreatment with MEM (18 mg/kg s.c.) and atropine sulfate (16 mg/kg s.c.), 60 min and 15 min, respectively, before DFP injection prevented the increase in citrulline and muscle hyperactivity and the decrease in ATP and PCr. These data suggest that free radical reactions by depleting high-energy phosphates may be initiating the cascade of events leading to myotoxicity during DFP-induced muscle hyperactivity.

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“…Indeed, even chronic low‐level exposure to dichlorvos raises mitochondrial calcium levels, impairs various complexes of the electron transport chain (ETC), decreases mitochondrial SOD, and induces apoptotic death . Mitochondrial complexes I, II, III, and IV of the ETC are known to be inhibited by acute exposure to OP or surrogate OP agents, and exposure to DFP has been shown to significantly deplete ATP levels within the hippocampus and amygdala . Seizures create a large ATP demand, and, when this is coupled with inhibition of aspects of the ETC, the result is impaired energy production and the generation of excessive ROS, specifically O 2 •− and H 2 O 2 .…”

Section: Mechanisms Of Ros Production In Op Toxicitymentioning

confidence: 99%

“…30 Mitochondrial complexes I, II, III, and IV of the ETC are known to be inhibited by acute exposure to OP or surrogate OP agents, and exposure to DFP has been shown to significantly deplete ATP levels within the hippocampus and amygdala. 30,[55][56][57] Seizures create a large ATP demand, and, when this is coupled with inhibition of aspects of the ETC, the result is impaired energy production and the generation of excessive ROS, specifically O 2…”

Section: Excitotoxicitymentioning

confidence: 99%

The role of oxidative stress in organophosphate and nerve agent toxicity

Pearson

Patel

2016

Annals of the New York Academy of Sciences

131

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Organophosphate nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent organophosphate toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to organophosphate agents. Key findings of these studies include alterations in mitochondrial function and increased free radical–mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in organophosphate neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of organophosphate-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures.

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Effects of organophosphorous compounds on fatty acid compositions and oxidative phosphorylation system in the brain of rats

Cited by 13 publications

References 19 publications

Anticholinesterase Toxicity and Oxidative Stress

Anticholinesterase Toxicity and Oxidative Stress

Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity

The role of oxidative stress in organophosphate and nerve agent toxicity

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