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

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