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- Baidya, Anurag T. K., et al.
(författare)
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Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors
- 2023
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 14:4, s. 749-765
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Tidskriftsartikel (refereegranskat)abstract
- Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimer's disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC50 values of 0.1, 1.5, and 5.3 mu M, respectively. In this study we utilize a battery of computational tools to perceive a mechanistic insight into the molecular interaction of PPIs with the ChAT binding pocket that may further help in designing novel ChAT ligands. Various in-silico tools make it possible for us to elucidate the binding interaction, conformational stability, and dynamics of the protein-ligand complexes within a 200 ns time frame. Further, the binding free energies for the PPI-ChAT complexes were explored. The results suggest that the PPIs exhibit equal or higher binding affinity toward the ChAT catalytic tunnel and are stable throughout the simulated time and that the pyridine ring of the PPIs interacts primarily with the catalytic residue His324. A free energy landscape analysis showed that the folding process was linear, and the residue interaction network analysis can provide insight into the roles of various amino acid residues in stabilization of the PPIs in the ChAT binding pocket. As a major factor for the onset of Alzheimer's disease is linked to cholinergic dysfunction, our previous and the present findings give clear insight into the PPI interaction with ChAT. The scaffold can be further simplified to develop novel ChAT ligands, which can also be used as ChAT tracer probes for the diagnosis of cholinergic dysfunction and to initiate timely therapeutic interventions to prevent or delay the progression of AD.
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| 2. |
- Kumar, Amit, et al.
(författare)
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Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery : A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index
- 2020
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Ingår i: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 182
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have linked prolonged use of the most commonly prescribed proton pump inhibitors (PPIs) with declined human sperm function and infertility. Here, we report for the first time the most plausible underlying mechanism for this unwarranted secondary mode of action. We followed up on a recent serendipitous discovery in our laboratory regarding PPIs' off-target action and performed detailed pharmacodynamic analyses by combining in silico and in vitro studies to determine the off-target effect of one of the most commonly used PPI, esomeprazole, on the key human acetylcholine biosynthesizing enzyme, choline acetyltransferase (ChAT; EC 2.3.1.6). A pivotal enzyme in the spermic cholinergic system that governs the sperm motility, concentration and quality. Our results were conclusive and showed that both the racemic form, omeprazole and its pure S-enantiomer, esomeprazole, acted as potent mixed-competitive inhibitor of human ChAT with a global inhibition constant (Ki) of 88 nM (95%CI: 10-167 nM) for esomeprazole and 178 nM (95%CI: 140-230 nM) for the racemic drug omeprazole. Most importantly, esomeprazole substantially reduces both total number of motile sperm (by 36%, p < 0.001; and 21% p < 0.0001, at 10 and 100 nM, respectively) as well as the total number of sperm with progressive motility (by 42% p < 0.0016 and by 26% p < 0.0001, respectively) after 60 min relative to 20 min incubation in our ex vivo functional assay performed on ejaculated human sperm. In conclusion, this study presents a completely new perspective regarding PPIs secondary mode of action/unwarranted side effects and calls for further mechanistic and larger clinical studies to elucidate the role of PPIs in infertility.
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| 3. |
- Kumar, Rajnish, et al.
(författare)
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Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme - A plausible missing link for their association with incidence of dementia
- 2020
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Ingår i: Alzheimer's & Dementia. - : WILEY. - 1552-5260 .- 1552-5279. ; 16:7, s. 1031-1042
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia.Methods: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh).Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations.Discussion: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis.
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| 4. |
- Xu, Hong, et al.
(författare)
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Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimers dementia
- 2023
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Ingår i: Kidney International. - : ELSEVIER SCIENCE INC. - 0085-2538 .- 1523-1755. ; 103:1, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimers dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression.
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