Table 2. Emerging targets for CE treatment.
|
Pharmacology
Agents |
Targets | Models | Relevant Mechanisms | References |
|---|---|---|---|---|
| Bumetanide | NKCC1 inhibitor | (1) Astrocyte swelling in vitro model of FPI (2) TBI mice (3) Spinal cord injury mice |
Bind inside the translocation cavity of NKCC1 to inhibit it from an extracellular location. | [172, 175-177] |
| Glibenclamide | SUR1-TRPM4 Inhibitor | (1) Freshly isolated type R1 astrocytes from adult rat brain (2) Humans |
Affects SUR1 kinetics rather than blocking the channel pore directly. | [48, 197] |
| Aquaporumab | AQP4 monoclonal antibody |
- | - | - |
| AER-270 | AQP4 inhibitor | Water intoxication mice | Inhibits AQP4. | [171] |
| AER-271 | AQP4 inhibitor | MCAO mice | Inhibits AQP4. | [171] |
| Amiloride | Mechanogated membrane ion channels inhibitor | TBI mice | Blocks the Na+ channel, the Na+/H+ antiport, and the Na+/Ca2+ exchanger. | [198-201] |
| Gentamicin | Inhibits Ca2+ channel TRPV5. | |||
| Gadolinium | Alters the packing and lateral pressure of anionic lipids. | |||
| Heparin | Glycocalyx | SE mice | Ameliorates glycocalyx degradation. | [202] |
| SR 49059 | V1a receptor antagonist |
TBI mice | Competitively inhibits V1a receptor. | [203, 204] |
| ML-7 | MLCK inhibitor | TBI mice | Inhibits MLCK phosphorylation. | [205] |
| SB-3CT | MMP-2/9 inhibitor | MCAO mice | Alters their structures | [206, 207] |
| Fenofibrate | PPAR-α agonist | TBI mice | Reduces ICAM-1, iNOS (NOS2), MMP-9, and markers of oxidative stress. | [208, 209] |
| Pioglitazone/ Rosiglitazone |
PPAR-γ agonist | TBI mice | Reduces IL-6, MCP-1 and ICAM-1. | [210] |
| Curcumin | Multiple targets | (1) SAH mice (2) HIBD mice (3) Humans |
(1) Upregulates tight junction proteins (ZO-1, occludin, claudin-5), upregulates glutamate transporter-1 (2) Inhibits ICAM-1/VCAM-1, inflammatory cytokines (IL-1β, IL-6, TNF, NF-κB) and microglial activation (3) Downregulates VEGF, AQP4 and MMP-9 |
[211-215] |
| VEGI | VEGF inhibitor | TBI mice | (1) Reduces tissue loss and microgliosis. (2) Upregulates tight junction proteins (claudin-5, ZO-1, and occluding) |
[216] |
| Bevacizumab | VEGF monoclonal antibody |
Humans | Relieves glioblastoma peri-tumoral edema. | [217] |
| AAV8-VEGF-C | Meningeal lymphangiogenesis | HE mice | (1) Increases meningeal lymphangiogenesis (2) Reduces microglia activation |
[181] |
| AAV1-CMV- mVEGF-C |
Meningeal lymphangiogenesis | FAD mice | Increases meningeal lymphangiogenesis | [111] |
| Recombinant VEGF-C |
Meningeal lymphangiogenesis | (1) APP/PS1 transgenic mice (2) AD mice |
Increases meningeal lymphangiogenesis | [182] |
| MAZ51 | CLNs | FCI mice | (1) VEGFR-3 tyrosine kinase inhibitor (2) Reduces inflammatory factors (CCL28, CCL2, TNF-α, IL-1β) and brain injury |
[105] |
Abbreviations: AD, Alzheimer’s disease; AQP4, aquaporin-4; CLN, cervical lymph nodes; FCI, focal cerebral ischemia; FPI, fluid percussion injury; HE, hepatic encephalopathy; HIBD, hypoxia-ischemic brain damage; MCAO, middle cerebral artery occlusion; NKCC1, Na+–K+–2Cl- cotransporter1; NOS, nitric oxide synthase; SUR1, sulfonylurea receptor 1; SE, status epilepticus; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury; TRPM4, transient receptor potential melatonin 4; VEGF, vascular endothelial growth factor.