Abstract
Background: Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent research suggests that disruptions in calcium (Ca²⁺) homeostasis play a crucial role in the pathogenesis of AD. Verapamil, a calcium channel blocking drug, may be a promising medication for preventing cognitive decline and dementia associated with AD.
Methods: We used MedWatch data to assess the relationship between verapamil and risk of dementia. MedWatch is the Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program. To evaluate the role of verapamil in calcium homeostasis, we studied verapamil interaction with septins. Septins are membrane-interacting, guanosine triphosphate (GTP) binding proteins with a highly conserved domain structure. Septins are involved in several cellular functions, such as membrane dynamics, cytoskeleton organization, and cytokinesis. Pharmacological modulation of septin 6 has been shown to restore calcium homeostasis and is neuroprotective in models of AD. We performed in silico molecular docking studies to determine where verapamil docks to human septin trimer 2/6/7.
Results: Verapamil use was associated with a significantly reduced risk of AD (Proportional Reporting Ratio PRR 0.581). For comparison with verapamil, we evaluated risk of dementia associated with ibuprofen. We found that ibuprofen is related to a significantly reduced risk of AD (PRR 0.42) that was comparable to verapamil. Verapamil docked to human septin trimer 2/6/7 within septin 7, which has been associated with AD. Verapamil docked to the central GTP-binding domain of septin 7, which provides the two inter-subunit interfaces (named G and NC) necessary for filament assembly.
Conclusion: Strategies aimed at restoring Ca²⁺ balance, among them verapamil treatment, hold promise for mitigating the progression of AD and improving cognitive function.