DIM Therapy for NET-Resistant Mechanical Thrombectomy
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Solution Overview
Problem
Current treatments for acute ischemic stroke (AIS) using mechanical thrombectomy (MT) are hindered by the formation of neutrophil extracellular traps (NETs), which cause resistance to thrombolytic therapy, incomplete clot removal, and poor long-term outcomes due to uncontrolled thrombus propagation and adherence to blood vessel walls.
Innovation Solution
Administering 3,3′-diindolylmethane (DIM) or its analogs, potentially in a self-microemulsifying drug delivery system (SMEDDS) formulation, to inhibit NET formation and propagation, thereby enhancing the effectiveness of MT and improving clinical outcomes in AIS and acute myocardial infarction (AMI).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mechanical thrombectomy (MT) is performed to remove thrombus, then clot removal is achieved, but NET formation causes resistance to thrombolytic therapy and incomplete clot removal
Solution Approach 1:
The patent applies preliminary anti-action by administering 3,3'-diindolylmethane (DIM) before or during mechanical thrombectomy to prevent NET formation in advance. DIM inhibits the formation of neutrophil extracellular traps (NETs) by blocking the enzymatic activity of neutrophil elastase and peptidyl arginine deiminase type 4 (PAD4), thereby preventing the immunopathologic process that leads to thrombus propagation and resistance to thrombolytic therapy before the thrombectomy procedure begins
Solution Approach 2:
The patent uses 3,3'-diindolylmethane (DIM) as an intermediary substance that mediates between the thrombectomy procedure and the NET formation process. DIM acts as a pharmacological mediator that selectively inhibits NET formation without affecting the mechanical thrombectomy procedure itself, allowing the thrombectomy to proceed more effectively by reducing NET-related resistance and thrombus propagation
2Reliability
If multiple device passes are performed to remove thrombus, then complete clot removal is attempted, but the number of device passes increases and MT time extends
Solution Approach 1:
The patent applies preliminary action by administering 3,3'-diindolylmethane (DIM) before the mechanical thrombectomy procedure to pre-inhibit NET formation and reduce thrombus propagation. This preliminary pharmacological intervention prepares the thrombus for more effective removal by reducing the immunopathologic processes that make the thrombus more adherent and resistant to mechanical removal, thereby reducing the need for multiple device passes and extending the procedure time
3Reliability
If tPA therapy is administered to dissolve fibrin clots, then thrombolysis is achieved, but tPA resistance occurs due to NET formation
Solution Approach 1:
The patent applies the blessing in disguise principle by using 3,3'-diindolylmethane (DIM) to convert the harmful effect of NET formation into a beneficial outcome. Instead of allowing NETs to cause tPA resistance and thrombus propagation, DIM selectively inhibits NET formation by blocking the enzymatic activity of neutrophil elastase and PAD4, thereby converting the potential harm of uncontrolled NETosis into the benefit of enhanced thrombolytic sensitivity and reduced thrombus propagation while preserving the body's innate immune defense mechanisms
Data Source
AI summary
Provided herein are methods of enhancing mechanical thrombectomy during endovascular therapy for acute thrombosis using 3,3′-diindolylmethane.