OP/nerve agents are still considered as important chemicals acting on living organisms and are widely used. They are characterized according to their action as compounds influencing cholinergic nerve transmission via inhibition of AChE. Modeling of this action and extrapolation of experimental data from animals to humans is more possible for highly toxic agents than for the OP. The symptoms of intoxication comprise nicotinic, muscarinic, and central symptoms; for some OP/nerve agents, a delayed neurotoxicity is observed. Cholinesterases (AChE and BuChE) are characterized as the main enzymes involved in the toxic effect of these compounds, including molecular forms. The activity of both enzymes (and molecular forms) is influenced by inhibitors (reversible, irreversible, and allosteric) and other factors, such as pathological states. There are different methods for cholinesterase determination; however, the most frequent is the method based on the hydrolysis of thiocholine esters and subsequent detection of free SH-group of the released thiocholine. The diagnosis of OP/nerve agent poisoning is based on anamnesis, the clinical status of the intoxicated organism, and on cholinesterase determination in the blood. For nerve agent intoxication, AChE in the red blood cell is more diagnostically important than BuChE activity in the plasma. This enzyme is a good diagnostic marker for intoxication with OP pesticides. Some other biochemical examinations are recommended, especially arterial blood gas, blood pH, minerals, and some other specialized parameters usually not available in all clinical laboratories. These special examinations are important for prognosis of the intoxication, for effective treatment, and for retrospective analysis of the agent used for exposure. Some principles of prophylaxis against OP/nerve agent poisoning comprising the administration of reversible cholinesterase inhibitors such as pyridostigmine (alone or in combination with other drugs), scavengers such as preparations of cholinesterases, some therapeutic drugs, and possible combinations are given. Basic principles of the treatment of nerve agent OP poisoning are described. They are based on the administration of anticholinergics (mostly atropine but some other anticholinergics can be recommended) as a symptomatic treatment, cholinesterase reactivators as a causal treatment (different types but without a universal reactivator against all OP/nerve agents) as the first aid and medical treatment, and anticonvulsants, preferably diazepam though some other effective benzodiazepines are available. New drugs for the treatment are under experimental study based on new approaches to the mechanism of action. Future trends in the complex research of these compounds, which is important not only for the treatment of intoxication but also for the quantitative and qualitative increase of our knowledge of toxicology, neurochemistry, neuropharmacology, clinical biochemistry, and analytical chemistry in general, are characterized.

Organophosphates⧸Nerve Agent Poisoning: Mechanism of Action, Diagnosis, Prophylaxis, And Treatment

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce n...

https://www.tandfonline.com/doi/pdf/10.1080/10408440802272158

Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment.

Bacteria sense and respond to a wide range of physical and chemical signals. Central to sensing and responding to these signals are two-component systems, which have a sensor histidine kinase (SK) and a response regulator (RR) as basic components. Here we review the different molecular mechanisms by which these signals are integrated and modulate the phosphorylation state of SKs. Apart from the basic mechanism, which consists of signal recognition by the SK that leads to an alteration of its autokinase activity and subsequently a change in the RR phosphorylation state, a variety of alternative modes have evolved. The biochemical data available on SKs, particularly their molecular interactions with signals, nucleotides, and their cognate RRs, are also reviewed.

Bacterial Sensor Kinases: Diversity in the Recognition of Environmental Signals

Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer’s disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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Cholinesterases, a target of pharmacology and toxicology

Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development--a study of molecular forms.

Effects of Diisopropylfluorophosphate on Brain Cholinergic Systems of Rats at Early Developmental Stages

BACKGROUND AND OBJECTIVE: A novel non-enveloped DNA virus, called TT virus (TTV), has been reported to be associated with post-transfusion hepatitis of unknown etiology. Although its clinical role still remains obscure, its presence in blood donations might cause problems. It, therefore, appeared of interest to investigate TTV prevalence in voluntary blood donors. DESIGN AND METHODS: A total of 595 Italian blood donors with and without elevated serum alanine aminotransferase (ALT) levels were tested by polymerase chain reaction using two sets of semi-nested primers that amplify the well-known region in the N22 clone. The amplified products were then sequenced to assess the genotype by phylogenetic and restriction fragment length polymorphism analyses. RESULTS: The prevalence of TTV in blood donors was 5+/-1.9% (25 out of 500) with a 95% confidence limit. A similar prevalence was found in 95 selected blood donors with increased ALT levels. A viral load of 10(3)-10(4) viral DNA molecules/mL was found, thus indicating a rather narrow range of variability. A phylogenetic tree built up on the basis of 210 base sequences of ORF1 allowed isolates to be classified into 2 groups corresponding, at least, to two of the putatives TTV genotypes, group 1 and group 2 of Okamoto's classification. A similar classification was also obtained by site restriction enzyme analysis. INTERPRETATION AND CONCLUSIONS: The results show that TTV infection is present among Italian blood donors. No significant difference in prevalence of TTV infection was found between patients with normal and increased ALT, making the association between TTV infection and human hepatitis questionable.

/pdf/prevalence-of-tt-viral-dna-in-italian-blood-donors-with-and-2wg1g2ucs4.pdf

Prevalence of TT viral DNA in italian blood donors with and without elevated serum ALT levels: molecular characterization of viral DNA isolates

Ubiquitin (Ub) is a small 76-residue protein, involved in intracellular protein degradation through a specific ATP-dependent system, which uses Ub as a tag to label proteins committed to be hydrolyzed by a specific 26 S protease. PGP-9.5 is another important component of the Ub system, i.e. a neuron-specific carboxyl-terminal hydrolase, which recycles Ub from Ub-polypeptide complexes. We have investigated the expression of Ub and PGP-9.5 in rat hippocampal neurons in an early phase of reperfusion in a model of transient global brain ischemia/hypoxia (bilateral occlusion of common carotid arteries for 10 min accompanied by mild hypoxia—15% O2—for 20 min), by means of immunohistochemical methods using light and electron microscopy. The intensity of Ub and PGP-9.5 immunoreactivity was evaluated by image analysis. We have detected a marked increase of Ub immunoreactivity (UIR) in neurons of CA1, CA2, CA3, CA4, and dentate gyrus subfields 1 hr after ischemia/hypoxia (but not after hypoxia only), statistically significant as confirmed by image analysis. Such increase in immunoreactivity in ischemic/hypoxic rats was localized essentially in the nuclei of hippocampal neurons. There were no changes in PGP-9.5 immunoreactivity. The data suggest that in the present model of rat brain ischemia/hypoxia Ub is involved in the neuronal stress response.

Ubiquitin-mediated stress response in a rat model of brain transient ischemia/hypoxia.

Transient global brain hypoxia-ischemia in adult rats: Neuronal damage, glial proliferation, and alterations in inositol phospholipid hydrolysis

A previous study conducted in this laboratory revealed a decrease in total cholinesterase (total ChE) in the cerebral cortex, hippocampus and striatum in aged rats (24 months) of various strains, as compared with young animals (3 months). The purpose of the present experiments was to extend the study to other brain areas (hypothalamus, medulla-pons and cerebellum) and to assess whether this decrease was dependent on the reduction of either specific acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) or both. By using ultracentrifugation on a sucrose gradient, the molecular forms of AChE were evaluated in all the brain areas of young and aged Sprague-Dawley rats. In young rats the regional distribution of total ChE and AChE varied considerably with respect to BuChE. The age-related loss of total ChE was seen in all areas. Although there was a reduction of AChE and, to somewhat lesser extent, of BuChE in the cerebral cortex, hippocampus, striatum, and hypothalamus (but not in the medulla-pons or the cerebellum), the ratio AChE/BuChE was not substantially modified by age. Two molecular forms of AChE, namely G4 (globular tetrameric) and G1 (monomeric), were detected in all the brain areas. Their distribution, expressed as G4/G1 ratio, varied in young rats from about 7.5 for the striatum to about 2.0 for the medulla-pons and cerebellum. The age-related changes consisted in a significant and selective loss of the enzymatic activity of G4 forms in the cerebral cortex, hippocampus, striatum, and hypothalamus, which resulted in a significant decrease of the G4/G1 ratio. No such changes were found in the medullapons or the cerebellum. Since G4 forms have been proposed to be present presynaptically, their age-related loss in those brain areas where acetylcholine plays an important role in neurotransmission may indicate an impairment of presynaptic mechanisms.

Guillermo M. Bisso

Papers

Effects of Diisopropylfluorophosphate on Brain Cholinergic Systems of Rats at Early Developmental Stages

Prevalence of TT viral DNA in italian blood donors with and without elevated serum ALT levels: molecular characterization of viral DNA isolates

Ubiquitin-mediated stress response in a rat model of brain transient ischemia/hypoxia.

Transient global brain hypoxia-ischemia in adult rats: Neuronal damage, glial proliferation, and alterations in inositol phospholipid hydrolysis

Age-related changes in acetylcholinesterase and its molecular forms in various brain areas of rats.