Ashmi Patel

Introduction. Stroke outco me is dependent on several factors including the permeability of the blood-brain barrier (BBB) by matrix metalloproteases (MMPs).²  In ischemia, MMP-2 and MMP-9 degrade claudin-5, which facilitates the increased permeability of the BBB and decrease in tight junction proteins (TJPs).²  MMP-9 cleaves ZO-1 and degrades basal lamina proteins, which may result in an increased breakdown of tight junctions.²  Several therapies have been tested in recent years to block these detrimental actions of MMPs during ischemia. Methods.  To test the integrity of the BBB, MMP-12 knockdown mice were subjected to middle cerebral artery occlusion (MCAO).¹  A study using primate MCAO models was also used in conjunction with a cerebrospinal fluid (CSF) sampling method to test the BBB.⁶  To test actin depolymerizing factor mutant (ADFm) as treatment, the transient focal cerebral ischemia and reperfusion model was used with neutrophil extraction.⁴  To test Tregulatory cells (Tregs) as treatment, the MCAO model was used and mice were administered with tPA and T_regs, then analyzed by an in vitro endothelial cell-based model.³ To test nicotinamide mononucleotide (NMN) as treatment, the MCAO model was used and tPA and NMN were given at the time of reperfusion.⁵  Results.  The study with MMP-12 knockdown mice solidifies the hypothesis that MMP-12 has an effect on BBB damage during ischemia and could be a potential therapeutic agent for ischemia.¹  The primate model study highlights the multifaceted nature of BBB breakdown signaling and highlights that no single MMP is the cause of all BBB breakdown.⁶  The ADFm study shows that treatment with ADFm could decrease actin polymerization and decrease the disassembly of TJPs, essentially counteracting the typical activity of MMPs, decreasing the extent of BBB destruction after ischemia and reperfusion, and improving long-term outcomes.⁴  The study regarding T_regs provides significant evidence that T_reg transfer can be an effective therapy for reducing risk of hemorrhage after delayed tPA treatment.³  The results from the NMN study show that treatment with NMN and tPA decreases the rate of hemorrhagic transformation through maintenance of the BBB.⁵  Conclusions.  A single MMP inhibitor has been deemed insufficient to counteract the effects of ischemic stroke.  Promising therapies that target upstream molecules include administration of ADFm, T_regs, and NMN.  Ideally, the possible therapy could also be used in conjunction with tPA to widen the window of tPA administration without increasing risk of hemorrhage.

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