Table 1.
Major strategies in experimental subarachnoid hemorrhage aimed at targeting neuroinflammation and/or microvascular dysfunction.
| Major Experimental Targets | Genetic or Pharmacologic Approach |
Results | Translated to SAH Patients |
Reference(s) |
|---|---|---|---|---|
| Pattern-Recognition Receptors | ||||
| Toll-like Receptor 4 (TLR4) | TLR4−/− mice | Decreased vasospasm and neuronal apoptosis on days 7 and 15 after SAH | Not applicable | (27) |
| TLR4 antagonists (IAXO-102, TAK-242) | Higher neurological scores and reduced brain water content at 24 hours compared to controls, reduced BBB disruption with decreased MMP-9 and preserved tight junctions | No | (45) | |
| Resident Cells of the CNS | ||||
| Microglia | Clodronate liposomes | Depletion of microglia results in significant ablation of vasospasm at day 7 and 15 in mice, reduced neuronal death at day 7 but not at day 15 compared to vehicle-treated controls | No | (27) |
| CS11b-HSVTK+/− mice | Depletion of microglia results in reduced neuronal cell death | Not applicable | (31) | |
| Pro-inflammatory Cytokines | ||||
| Interleukin-1 (IL-1) | IL-1 receptor antagonist (IL-1Ra) | In rodents, treatment resulted in decreased BBB breakdown and subsequent brain injury | Yes. The SCILSAH study has shown safety, tolerability, and effective reduction in peripheral inflammatory markers, supporting a Phase III clinical trial | (42–44) |
| Cellular Adhesion Molecules | ||||
| CD11/CD18 (includes LFA-1 and Mac-1, also known as CD11a/CD18 and CD11b/CD18, respectively) | Anti-LFA-1 antibody | Reduction in femoral artery spasm following blood exposure in rats | No | (63) |
| Anti-CD11/CD18 antibody | Reduction in non-human primate cerebral vasospasm from baseline angiography compared to vehicle-treated animals; Reduction of rabbit basilar artery spasm and increased peripheral white blood cell count | No | (64–66) | |
| Intercellular adhesion molecule-1 (ICAM-1) | Anti-ICAM-1 antibody | Reduction in rabbit basilar artery spasm, synergistic with effects of anti- CD18 Ab; reduction in femoral artery spasm following blood exposure in rats | No | (63,65) |
| Vascular adhesion protein-1 (VAP-1) | LJP-1586 | Inhibition of VAP-1 results in reduced leukocyte adhesion and infiltration, enhanced microvascular reactivity, and improved shortterm neurologic outcome | No | (67,69) |
| Peripheral Immune Cells | ||||
| Neutrophils | Anti-neutrophil serum | Reduction in leukocyte infiltration into CNS, preservation of pial arteriolar dilating function, and protection of neurobehavioral l function; reduction in vascular collagenase activity | No, may prolong bleeding time from ruptured artery based on preclinical data | (69,70) |
| Anti-Ly6G/C antibody | Reduction in middle cerebral artery (MCA) vasospasm and improved behavioral testing via Ymaze and Barnes maze tests; reduced cerebral inflammation and decreased impairment in long-term potentiation (LTP) at day 6 after SAH in mice | No | (68,71) | |
| Lymphocytes | Corticosteroids (Dexamethasone, Methylprednisolone, etc.) | Reduced alterations in contractile and cytoskeletal proteins of rabbit cerebral arteries; decreased CSF citrulline (contributor to NO production) and leukocytosis; mixed results related to effect on vasospasm | Yes, with conflicting results. Overall, no strong evidence of beneficial or adverse effect | (76–78,82) |
| Cyclosporine | Reduction in canine basilar artery vasospasm with prophylactic treatment; reduction in neuronal apoptosis and BBB disruption in mice with improved neurological outcome | Yes, with conflicting results. Some have shown improved neurological outcome while others have shown no effect on vasospasm or DCI | (79–81,83,84) | |
| Fingolimod (FTY-720) | Reduced intravascular leukocyte adhesion to pial venules, preserved pial arteriolar reactivity, improved neurological outcome | No | (85) | |
| Endogenous Vasoconstrictors | ||||
| Endothelin-1 (ET-1) | Clazosentan (ET-1 receptor antagonist) | Prophylactic treatment in rats prevented continued reduction in cerebral blood flow after acute hypoperfusion; reduced largeartery vasospasm but did not prevent formation of microthrombi, neuronal cell death, or loss of LTP | Yes, reduction in angiographic vasospasm but no statistically significant effect on morbidity, mortality, or functional outcome | (11,12,97,98) |
| 20-hydroxyeicosatetranoic acid (20-HETE) | TS-011, 17-octadecynoic acid, HET0016 (selective CYP450 inhibitors) | Pre-treatment resulted in faster recovery of cerebral blood flow in the acute setting following SAH; reversal of delayed vasospasm in vitro and in vivo | No | (163–165) |
| Endogenous Vasodilators | ||||
| Nitric Oxide (NO) | NO donors (Larginine, Snitrosoglutathione, sodium nitroprusside, transdermal nitroglycerin, etc.) | Improved CBF recovery, reduction in cerebral vasospasm, decreased glutamate excitotoxicity, and transient decrease in systemic blood pressure | Yes, with conflicting results. Side effects including systemic hypotension, headache, and rebound hypertension possible, limiting clinical use. | (135–137,140–143) |
| Inhaled NO | Reduction in microvascular constriction with limited effects on large artery spasms, decreased cerebral edema, hippocampal neuronal loss, and mortality; improved neurological outcome | No | (133) | |
| Phosphodiesterase (PDE)-V inhibitors (sildenafil) | Reduction of vasospasm and neuronal cell death with improved neurological outcome in mice | Yes, Phase I study demonstrate d safety and tolerability, with some data suggesting potential improvement of vasospasm | (144,145) | |
| Vascular smooth muscle cell (vSMC) relaxation | PDE-III inhibitors (milrinone) | Prevented angiographic vasospasm in canine model; improved CBF and neurobehavioral l outcome, reduced DCI in mice | Yes, reduction in delayed cerebral vasospasm warranting further study | (146–151) |
| Magnesium sulfate | Reduction of infarct size, reversal of vasospasm in vivo and in vitro, and improved cerebral blood flow recovery | Yes, MASH-II and IMAGES trials failed to show clinical benefit | (152–158) |