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Sulfonylurea Class of Antidiabetic Drugs Inhibit Acetylcholinesterase Activity: Unexplored Auxiliary Pharmacological Benefit toward Alzheimer's Disease.

ABSTRACT: Contemporary literature documents extensive research on common causative mechanisms, pathogenic pathways and dual effective remedies for Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM). Tolbutamide (TBM), chlorpropamide (CPM), and glyburide (GLY) are three sulfonylurea antidiabetic drugs of different generations. All these drugs were found to exhibit moderate to strong inhibitory efficiency on the neurotransmitter degrading enzyme acetylcholinesterase (AChE) with GLY (IC₅₀ = 0.74 ± 0.02 μM) being the most potent, followed by CPM (IC₅₀ = 5.72 ± 0.24 μM) and TBM (IC₅₀ = 28.9 ± 1.60 μM). Notably, the inhibition efficiency of GLY is even comparable with the FDA approved AD drug, donepezil (DON). The larger size of GLY spans almost the full gorge of AChE ranging from catalytic active site (CAS) to the peripheral active site (PAS) with relatively strong binding affinity (6.0 × 10⁵ M^-1) and acts as a competitive inhibitor for AChE. On the other hand, while they show relatively weak binding ((2-6) × 10⁴ M^-1), both CPM and TBM act as noncompetitive binders. While these two drugs can bind to PAS, MD simulation results predict an alternative noncompetitive inhibition mechanism for CPM. These results open the possibility of repurposing the antidiabetic drugs, particularly GLY, in the treatment of AD. The consequential side effect of excess acetylcholine production, due to the administration of these drugs to AD-unaffected patients, can be rectified by using colloidal gold and silver nanofluids as potential AChE activity boosters.

SUBMITTER: Baruah P

PROVIDER: S-EPMC7887854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough considered one of the most effective interventions for substance use disorders (SUD), the widespread implementation of contingency management (CM) has remained limited. In more recent years there has been surge in the implementation of CM to address increasing rates of substance use. Prior studies at the provider-level have explored beliefs about CM among SUD treatment providers and have tailored implementation strategies based on identified barriers and training needs, to promote implementation of CM. However, there have been no implementation strategies that have actively sought to identify or address potential differences in the beliefs about CM that could be influenced by the cultural background (e.g., ethnicity) of treatment providers. To address this knowledge gap, we examined beliefs about CM among a sample of inpatient and outpatient SUD treatment providers.MethodsA cross-sectional survey of SUD treatment providers was completed by 143 respondents. The survey asked respondents about their attitudes toward CM using the Contingency Management Beliefs Questionnaire (CMBQ). Linear mixed models examined the effect of ethnicity (non-Hispanic White and Hispanic) on CMBQ subscale (general barriers, training-related barriers, CM positive-statements) scores.ResultsFifty-nine percent of respondents to the CMBQ self-identified as non-Hispanic White and 41% as Hispanic. Findings revealed that treatment providers who identified as Hispanic had significantly higher scores on the general barriers (p < .001) and training-related barriers (p = .020) subscales compared to the non-Hispanic White treatment providers. Post-hoc analyses identified differences in the endorsement of specific individual scale items on the general barriers (e.g., CM interventions create extra work for me) and training-related (e.g., I want more training before implementing CM) subscales.ConclusionsDissemination and implementation strategies for CM need to consider equity-related factors at the provider-level that may be associated with the adoption and uptake of CM.

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Sulfonylurea Class of Antidiabetic Drugs Inhibit Acetylcholinesterase Activity: Unexplored Auxiliary Pharmacological Benefit toward Alzheimer's Disease.

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