Abstract
Anticholinergic drugs can be used as a treatment for many diseases. However, anticholinergic drugs are also known for their cognition-related side effects. Recently, there has been an increasing number of reports indicating a positive association between exposure to anticholinergic drugs and Alzheimer's disease (AD). Our novel study provides evidence of interactions between two representative anticholinergic drugs [Chlorpheniramine (CPM), a common antihistamine, and Trazodone (TRD), an antidepressant] with neuroprotective amyloid-beta (Aβ) chaperone, lipocalin-type prostaglandin D synthase (L-PGDS) and the amyloid beta-peptide (1–40). Here, we demonstrate that CPM and TRD bind to L-PGDS with high affinity where chlorpheniramine exhibited higher inhibitory effects on L-PGDS as compared to Trazodone. We also show that the interactions between the drug molecules and Aβ(1–40) peptides result in a higher fibrillar content of Aβ(1–40) fibrils with altered fibril morphology. These altered fibrils possess higher cytotoxicity compared to Aβ(1–40) fibrils formed in the absence of the drugs. Overall, our data suggest a mechanistic link between exposure to anticholinergic drugs and increased risk of Alzheimer's disease via inhibition of the neuroprotective chaperone L-PGDS and direct modification of Aβ amyloid morphology and cytotoxicity.
Highlights
Anticholinergic (AC) drugs can be defined as drugs directly targeting the muscarinic receptors in the cholinergic transmission pathway or drugs that contain anticholinergic properties (Coupland et al, 2019; Joung et al, 2019)
We showed that lipocalin-type prostaglandin D synthase (L-PGDS) inhibits nucleation and propagation of Ab fibrils and is capable of disaggregation of pre-formed Ab amyloids in vitro as well as in Alzheimer's disease (AD) brain extracts releasing proteins typically associated with amyloid plaques (Kannaian et al, 2019)
We discovered that AC drugs such as CPM and TRD bind to lipophilic carriers such as L-PGDS with relatively high affinities and disrupt its neuroprotective function important for the Ab homeostasis
Summary
Anticholinergic (AC) drugs can be defined as drugs directly targeting the muscarinic receptors in the cholinergic transmission pathway or drugs that contain anticholinergic properties (Coupland et al, 2019; Joung et al, 2019). This broad group of AC drugs can be used as a treatment for a wide range of diseases such as depression, an allergic reaction, and sleep (Joung et al, 2019). Most AC drugs are lipophilic which allows them to cross the blood-brain barrier (BBB) such as the firstgeneration antihistamine and anti-depressant to exert their effects in the brain (Chancellor et al, 2012).
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