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Verapamil Prevents Development of Cognitive Impairment in an Aged Mouse Model of Sporadic Alzheimer’s Disease

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Abstract

Currently, dementia is the only leading cause of death that is still on the rise, with total costs already exceeding those of cancer and heart disease and projected to increase even further in the coming years. Unfortunately, there are no satisfactory treatments and attempts to develop novel, more effective treatments have been extremely costly, albeit unsuccessful thus far. This has led us to investigate the use of established drugs, licensed for other therapeutic indications, for their potential application in cognitive disorders. This strategy, referred to as “drug repositioning,” has been successful in many other areas including cancer and cardiovascular diseases. To our knowledge, this is the first study to investigate the effects of long-term treatment with verapamil, a calcium channel blocker commonly prescribed for various cardiovascular conditions and recently applied for prevention of cluster headaches, on the development of cognitive impairment in aged animals. Verapamil was studied at a low dose (1mg/kg/d) in a mouse model of sporadic Alzheimer’s disease (sAD). Oral treatment with verapamil or vehicle was started, 24 h post-intracerebroventricular (ICV) streptozotocin/(STZ), in 12-month-old animals and continued for 3 months. Cognitive function was assessed using established tests for spatial learning, short-term/working memory, and long-term/reference memory. Our findings demonstrate that long-term low-dose verapamil effectively prevents development of ICV/STZ-induced cognitive impairment. It mitigates the astrogliosis and synaptic toxicity otherwise induced by ICV/STZ in the hippocampus of aged animals. These findings indicate that long-term, low-dose verapamil may delay progression of sAD in susceptible subjects of advanced age.

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Data Availability

The data generated and analyzed in this study will be made available from the corresponding author on reasonable request.

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Funding

This work were supported by the National Institute of Health [R01-NS097800 (TI)] and Department of Anatomy Neurobiology, UTHSC Memphis TN (TI).

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Heba A. Ahmed, Saifudeen Ismael & Tauheed Ishrat

  2. Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Golnoush Mirzahosseini & Tauheed Ishrat

  3. Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Tauheed Ishrat

  4. College of Medicine, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA

    Tauheed Ishrat

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  1. Heba A. Ahmed
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  2. Saifudeen Ismael
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Contributions

HA conducted behavior tests, monitored parameters, analyzed data, prepared the figures and drafted the manuscript; SI performed surgeries, prepared treatments, analyzed data and reviewed the manuscript; G.M. assisted with tissue collection, processing and western blot; and T.I designed and oversaw the whole project including experimental design, randomization, data analysis, and managing of the manuscript.

Corresponding author

Correspondence to Tauheed Ishrat.

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All procedures performed in studies involving animals were approved by the institutional animal Committee at UTHSC in full accordance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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The authors declare that they have no conflict of interest.

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Ahmed, H.A., Ismael, S., Mirzahosseini, G. et al. Verapamil Prevents Development of Cognitive Impairment in an Aged Mouse Model of Sporadic Alzheimer’s Disease. Mol Neurobiol 58, 3374–3387 (2021). https://doi.org/10.1007/s12035-021-02350-9

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