acetylcholine metabolism
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Author(s):  
Dusty R. Miller ◽  
Ethan S. McClain ◽  
James N. Dodds ◽  
Andrzej Balinski ◽  
Jody C. May ◽  
...  

Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to predict biological responses remains. Here, we present a platform that combines a model organ-on-chip neurovascular unit (NVU) with targeted mass spectrometry (MS) and electrochemical analysis to assess the impact of organophosphate (OP) exposure on blood-brain barrier (BBB) function. Using the NVU to simulate exposure, an escalating dose of the organophosphate chlorpyrifos (CPF) was administered. With up to 10 μM, neither CPF nor its metabolites were detected across the BBB (limit of quantitation 0.1 µM). At 30 µM CPF and above, targeted MS detected the main urinary metabolite, trichloropyridinol (TCP), across the BBB (0.025 µM) and no other metabolites. In the vascular chamber where CPF was directly applied, two primary metabolites of CPF, TCP and diethylthiophosphate (DETP), were both detected (0.1–5.7 µM). In a second experiment, a constant dose of 10 µM CPF was administered to the NVU, and though neither CPF nor its metabolites were detected across the BBB after 24 h, electrochemical analysis detected increases in acetylcholine levels on both sides of the BBB (up to 24.8 ± 3.4 µM) and these levels remained high over the course of treatment. In the vascular chamber where CPF was directly applied, only TCP was detected (ranging from 0.06 μM at 2 h to 0.19 μM at 24 h). These results provide chemical evidence of the substantial disruption induced by this widely used commercial pesticide. This work reinforces previously observed OP metabolism and mechanisms of impact, validates the use of the NVU for OP toxicology testing, and provides a model platform for analyzing these organotypic systems.





2021 ◽  
pp. 147518
Author(s):  
Donald A. Godfrey ◽  
Lissette Carlson ◽  
Jami L. Park ◽  
C. David Ross


2021 ◽  
Author(s):  
Verônica Farina Azzolin ◽  
Fernanda Barbisan ◽  
Ivo Emilio da Cruz Jung ◽  
Cibele Ferreira Teixeira ◽  
Euler Esteves Ribeiro ◽  
...  

In this chapter the following topics will be addressed: (1) actions of the cholinergic system in the nervous system, commenting on acetylcholine metabolism and acetylcholinesterase metabolism; (2) acetylcholinesterase inhibitors as subtitle in this topic: pharmacological characterization of pyridostigmine bromide, mechanism of action, and therapeutic effect of the drug; (3) use of pyridostigmine bromide in Persian Gulf War; and (4) potential effect of pyridostigmine bromide in oxidative stress, addressing as subtitle the influence of pyridostigmine bromide on the superoxide-hydrogen peroxide imbalance model. Studies indicate that the interaction between pyridostigmine bromide and stressors could trigger genotoxicity, the mechanism associated with the induction of oxidative stress that leads to this side effect of this drug; however, this discussion needs to be better elucidated and may be more discussed as there is interaction between the pyridostigmine bromide and an endogenous oxidative imbalance caused by it or even by the possible interaction of this with genetic variations present in the antioxidant metabolism.



2020 ◽  
Author(s):  
Calli Bennett ◽  
Jacalyn Green ◽  
Mae Ciancio ◽  
Joanna Goral ◽  
Lenore Pitstick ◽  
...  

AbstractBackgroundRecent evidence suggests that sex plays a role when there are deficiencies in one-carbon metabolism, however, the impact on brain tissue remains unknown.ObjectiveThe aim of the study was to examine the impact of sex differences and dietary folic acid deficiency on brain tissue in adult mice.MethodsMale and female C57Bl/6J mice were placed on a folic acid deficient (FD) or control diet (CD) at six weeks of age. Mice were maintained on these diets for six months, after which animals were euthanized and brain tissue and serum were collected for analysis. Serum folate levels were measured. In brain tissue, hippocampal volume and morphology including Cornu Ammonis 1 and 3 (CA1; CA3), and dentate gyrus thickness were measured. Apoptosis within the hippocampus was assessed using active caspase-3 immunofluorescence staining. Additionally, cortical acetylcholine metabolism was measured in brain tissue using immunofluorescence staining of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT).ResultsMale and female FD mice had reduced serum levels of folate. Both males and females maintained on a FD showed a decrease in the thickness of the hippocampal CA3 region. Interestingly, there was a sex difference in the levels of apoptosis within the CA1 region of the hippocampus. In cortical tissue, there were increased levels of neuronal ChAT and reduced levels of AChE in FD females and male mice.ConclusionsThe results indicated that FD impacts hippocampal morphology through increased apoptosis and changes acetylcholine metabolism within the cortex. The data from our study indicate a sex difference in apoptosis and differences in hippocampal morphology and choline metabolism as a result of dietary folic acid deficiency.



2018 ◽  
Vol 34 (3) ◽  
pp. 363-374 ◽  
Author(s):  
Cristina Eugenia Gallegos ◽  
Carlos Javier Baier ◽  
Mariana Bartos ◽  
Cristina Bras ◽  
Sergio Domínguez ◽  
...  


2015 ◽  
Vol 93 (1) ◽  
pp. 47-53 ◽  
Author(s):  
T.R. Anju ◽  
C.S. Paulose

Neonatal hypoglycemia limits the glucose supply to cells, affecting the function of brain due to its high energy demand. This can cause long-term consequences in brain function, leading to memory and cognitive deficits. The present study evaluated the cholinergic functional regulation in cerebral cortex of one month old rats exposed to neonatal hypoglycemia to understand the long-term effects of early life stress. Receptor binding and gene expression studies were done in the cerebral cortex to analyze the changes in total muscarinicreceptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, cholineacetyl transferase and acetylcholine esterase. Neonatal hypoglycemia decreased total muscarinic receptors (p < 0.001) with reduced muscarinic M1, M2, and M3 receptor genes (p < 0.001) in one month old rats. The reduction in acetylcholine metabolism is indicated by the downregulated cholineacetyl transferase, upregulated acetylcholine esterase, and decreased vesicular acetylcholine transporter expression. These alterations in cholinergic function in one month old rat brain indicates the longterm consequences of neonatal hypoglycemia in cortical function, which can contribute to the onset of many disease conditions in later stages of life.



Author(s):  
Konstanze Plaschke ◽  
Ann-Katrin Müller ◽  
Jürgen Kopitz


2013 ◽  
Vol 91 (5) ◽  
pp. 350-356 ◽  
Author(s):  
T.R. Anju ◽  
C.S. Paulose

Molecular processes regulating cholinergic functions play an important role in the control of respiration under hypoxia. Cholinergic alterations and its further complications in respiration due to hypoxic insult in neonatal rats and the effect of glucose, oxygen, and epinephrine resuscitation was evaluated in the present study. Receptor binding and gene expression studies were done in the corpus striatum to analyse the changes in total muscarinic receptors, muscarinic M1, M2, M3 receptors, and the enzymes involved in acetylcholine metabolism, choline acetyltransferase and acetylcholinesterase. Neonatal hypoxia decreased total muscarinic receptors with reduced expression of muscarinic M1, M2, and M3 receptor genes. The reduction in acetylcholine metabolism is indicated by the downregulated choline acetyltransferase and upregulated acetyl cholinesterase expression. These cholinergic disturbances were reversed to near control in glucose-resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. The present findings points to the cholinergic alterations due to neonatal hypoxic shock and suggests a proper resuscitation method to ameliorate these striatal changes.





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