NRF2 Activators for Oxidative Stress in Cerebral Small Vessel Disease
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There are no specific mechanistic treatments available for cerebral small vessel disease, which is a major cause of stroke and contributes significantly to cognitive decline and dementia, with a recent gene-mapping study identifying TRIM47 as a potential candidate.
Innovation Solution
The use of NRF2 activators, such as diroximel fumarate and dimethyl fumarate, to treat cerebral small vessel disease by administering a therapeutically effective amount, potentially through induction and maintenance regimens, to activate the NRF2 pathway and provide cytoprotection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If no specific mechanistic treatments are available for cerebral small vessel disease, then the disease progresses with stroke and cognitive decline, but introducing new treatments requires investigation of novel therapeutic targets and mechanisms
Solution Approach 1:
The patent introduces NRF2 activators as intermediary substances that mediate between the administered compound and the pathological processes of cerebral small vessel disease. These activators work through the KEAP1-NRF2-ARE pathway to induce cytoprotective effects, including antioxidant responses and anti-inflammatory effects, thereby treating the disease through a well-defined molecular intermediary mechanism
Solution Approach 2:
The patent utilizes parameter changes in the KEAP1-NRF2 pathway by administering NRF2 activators that modify the oxidation state and activation level of NRF2. This changes the transcriptional activity of antioxidant response elements, thereby altering the cellular redox state and providing cytoprotection against cerebral small vessel disease pathology
2Object-affected harmful factors
If NRF2 activators are used to treat cerebral small vessel disease, then cytoprotection and antioxidant effects are enhanced, but the mechanism requires understanding of the KEAP1-NRF2-ARE pathway
Solution Approach 1:
The patent exploits the feedback mechanism inherent in the KEAP1-NRF2-ARE pathway. NRF2 activators disrupt the KEAP1-NRF2 interaction, leading to NRF2 accumulation and translocation to the nucleus, where it binds to ARE elements and induces transcription of cytoprotective genes. This creates a positive feedback loop that amplifies the protective response against oxidative stress and inflammation
Solution Approach 2:
The patent converts the harmful oxidative stress and inflammation associated with cerebral small vessel disease into a beneficial protective response. By activating NRF2, the system induces antioxidant enzymes and anti-inflammatory pathways that counteract the original harmful effects, transforming the pathological oxidant burden into a protective adaptive response
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
NRF2 activators like diroximel fumarate and dimethyl fumarate can ameliorate symptoms of cerebral small vessel disease, including vascular cognitive impairment and dementia, by enhancing the NRF2 antioxidant pathway, thereby reducing oxidative stress and improving blood-brain barrier function.
Implementation Method 1
NRF2 activators like diroximel fumarate and dimethyl fumarate can ameliorate symptoms of cerebral small vessel disease, including vascular cognitive impairment and dementia, by enhancing the NRF2 antioxidant pathway, thereby reducing oxidative stress
Data Source
AI summary
Cerebral small vessel disease (SVD) is a leading cause of stroke and a major contributor to cognitive decline and dementia in the population. Evidences indicate that blood brain barrier dysfunction may play a significant role in VD pathogenesis. Recently, an inverse association of TRIM47 expression in brain and vascular tissues with extensive-SVD severity was reported in a human genome wide association study combined with summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers. Now, the inventors demonstrate TRIM47 is a key regulator of actin cytoskeleton organization through KEAP1/NRF2 signalling pathway and might be protective from oxidative stress in brain EC. In particular, the in vitro TRIM47 knockdown decreases directed EC migration and delays EC adhesion process with loss of actin cortical reorganization and focal adhesion contacts. Furthermore, RNA sequencing and BioID results indicate that TRIM47 knockdown in brain EC, represses the expression of genes associated with cytoskeleton and NRF2 antioxidant pathway through a potential interaction with KEAP1. Accordingly, the present invention relates to the use of Nrf2 activators for the treatment of SVD.