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      An organ-agnostic drug repurposing strategy for dementia: Pre-clinical validation of network pharmacology to treat cerebrovascular dysfunction and cognitive impairment

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            Abstract

            Age-related loss of cognitive capacity and neurodegeneration have a great socioeconomical impact on our rapidly aging population. Despite numerous hypotheses, the causes for phenotypes currently termed as vascular dementia (vaD) and Alzheimer’s disease (AD) remain largely unknown. Currently approved drugs for dementias do not target causative mechanisms and only offer symptomatic relief with mild efficacy. Therefore, the identification of dementia causal mechanisms and the development of mechanism-based curative strategies are urgently needed. One common causal disease mechanism recently identified among dementias, cardiovascular, metabolic, respiratory, and other neurological conditions is related to reactive oxygen species (ROS) and cyclic GMP signaling (ROCG) dysfunction [1,2]. In patients with both vaD and AD, the impairment of this signaling pathway plays a crucial role in endothelial dysfunction, leading to reduced cerebral blood flow (CBF), impaired blood brain barrier (BBB), vascular lesions, and to AD-associated pathology amyloid-beta plaques and hyperphosphorylation of tau [3-6]. Here, our aim is to validate the efficacy of a network pharmacology approach, using repurposed drugs targeting the ROCG signaling module, to treat cerebrovascular dysfunction and cognitive impairment in a clinically relevant animal model Specifically, we will use the transgenic NADPH oxidase 5 (NOX5) KI/ apolipoprotein E (ApoE) KO mouse fed with a sodium-rich diet. Rodents lack the NOX5 gene, thus its insertion in the mouse is key due to its major role in the ROCG signaling and its association with disrupted BBB integrity and memory loss [7,8]. ApoE is a positive modulator of endothelial nitric oxide (NO) production and, functionally, loss of ApoE in mice results in attenuation of NO-cGMP dependent endothelial relaxation and reduction of CBF [9-11]. The inclusion of a diet rich in sodium, which in humans is a life-style factor shown to negatively impact cognition, is relevant as this diet impacts endothelial function via increased NOX-derived ROS and decreased endothelial NO synthase activity, leading to attenuated NO-dependent vasodilation [12-14]. By combining the genetic insertion of NOX5, deletion of ApoE and a specific diet, we aim to model ROCG dysfunction and its associated dementia-relevant pathophysiological features. Our purpose is to set the basis for a subsequent phase IIa clinical trial based on this first-in-class mechanism-based treatment for a mechanism-based subgroup of MCI and dementia. Through this proof-of-concept pre-clinical study we aim to acquire the necessary scientific data for the delivery of an innovative drug repurposing strategy with strong potential for clinical application and rapid translation. If demonstrated to be effective, this approach could benefit a subset of patients with ROCG signaling dysfunction, most likely with symptoms beyond cognitive impairment and in other organs, to improve with high precision their quality of life.

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            Conference
            ScienceOpen
            29 August 2022
            Affiliations
            [1 ] Department of Pharmacology and Personalised Medicine, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht (The Netherlands)
            [2 ] Department of Neurology and Center for Translational Neuro-and Behavioral Sciences (C-TNBS), University Medicine Essen, Essen (Germany)
            Author notes
            Author information
            https://orcid.org/0000-0002-1332-8713
            Article
            10.14293/S2199-1006.1.SOR-.PPPLKEN3.v1
            f7d19e33-2b56-4373-b94d-243be6158575

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            RExPO22
            Maastricht, Netherlands
            2-3 September, 2022
            History
            : 29 August 2022
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            ScienceOpen


            Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
            Dementia,Drug repurposing ,Network pharmacology,Pre-clinical validation

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