Repurposing of Approved Cardiovascular Drugs against Ischemic Cerebrovascular Disease by Disease–Disease Associated Network-Assisted Prediction

Abstract

Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease-disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.

Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning

“…Decades of effort have gone into making in vitro BBB models, and the qualities of the models are improving, as mentioned previously, but the development of CNS drugs is still a major challenge [ 29 ]. The attempts to develop new treatments for CNS diseases too frequently meet costly and disappointing results and they require both long timespans and high expenditure [ 31 ]. However, the repurposing of safe existing drugs to new indications provides a cost-effective and time-saving alternative [ 30 , 31 ].…”

“…The attempts to develop new treatments for CNS diseases too frequently meet costly and disappointing results and they require both long timespans and high expenditure [ 31 ]. However, the repurposing of safe existing drugs to new indications provides a cost-effective and time-saving alternative [ 30 , 31 ]. Drug repositioning or repurposing uses the versatile properties of approved drugs to reassign then to a new purpose.…”

“…Vascular protection seems to be a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases and ischemic cerebrovascular diseases [ 31 ]. Vascular-function-related biological processes and pathways may be the key links between cardiovascular diseases and ischemic cerebrovascular diseases.…”

“…The attempts to develop new treatments for CNS diseases have costly and disappointing results and require a long period of time and high expenditure, whereas the repurposing of safe existing drugs provides a cost-effective and time-saving alternative [ 30 , 31 ]. Drug repositioning, also known as drug repurposing, is based on the promiscuous properties of approved drugs, which encourages the re-examination of marketed drugs for new indications, and is an alternative approach to speeding up drug discovery that has become increasingly popular in recent years [ 31 ]. To date, the conventional de novo drug discovery process requires an average of around 13-15 years and 2-3 billion US dollars to approve and launch a drug [ 32 , 33 ].…”

“…It is speculated that drug repurposing requires an average of 6.5 years and 300 million US dollars to approve and launch a drug [ 32 , 33 ]. The process has been applied to find potential new uses for approved drugs or compounds for various CNS diseases, including dementia, neurodegenerative diseases, acute stroke, cancer, rare or orphan diseases, and metabolic disorders, and as antiviral, anti-bacterial, and analgesic drugs [ 31 , 33 - 38 ]. In this review, the recent progress of in vitro BBB models have been introduced and drug repositioning for CNS diseases has been discussed [ 39 ].…”