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.

The Potential Effect of Insulin on AChE and Its Interactions with Rivastigmine In Vitro

“…Since the enzyme function is highly related to an active site and substrate structures, insulin alone most probably cannot easily change the structure-function relationship, which explains our result. Thus, the modulatory effect of insulin on the cholinergic system indicated in the literature might be explained by insulin-induced hypoglycemia in different brain regions, which causes a significant decrease in AChE activity [62], and by the insulin-enhancing effect on ACh synthesis through stimulating the expression of choline acetyltransferase [63]. Since the direct influence of insulin on AChE activity is unlikely based on our result, the precise mechanisms of insulin interaction with AChE remain to be determined by further studies.…”

Diabetes and its Complications

“…Baruah and co-workers investigated the effects of three sulfonylurea antidiabetic drugs on acetylcholinesterase, an important target in Alzheimer's disease. 9 They found a strong inhibitory effect of glyburide, which motivates further investigations of this drug or its derivatives in Alzheimer's disease. Riching et al provided a Review on the utility of approved diabetes treatments in Alzheimer's disease.…”

“…Low-dose captopril had a strong effect on several biomarkers of oxidative stress and may be useful to prevent cardiovascular disease in patients with type 2 diabetes. Baruah and co-workers investigated the effects of three sulfonylurea antidiabetic drugs on acetylcholinesterase, an important target in Alzheimer’s disease . They found a strong inhibitory effect of glyburide, which motivates further investigations of this drug or its derivatives in Alzheimer’s disease.…”

A Study on Methodologies of Drug Repositioning Using Biomedical Big Data: A Focus on Diabetes Mellitus

“…Despite particular cases that benefited from the use of chloroquine, it is difficult to be confident regarding the efficacy of a drug before similar effects are observed in large-scale studies [ 38 , 39 ]. Taking DM as an example, it appears that various antihyperglycemic therapies have other than hypoglycemic effects ( Table 2 ) [ 10 - 12 , 26 , 36 , 40 - 51 ]. In addition, other types of drugs are likely to help lower blood sugar levels in diabetic patients ( Table 3 ) [ 13 , 24 , 25 , 30 , 32 , 35 , 52 ].…”