Table 6.
Preclinical studies on potential therapeutic targets for PHE after ICH.
| Potential targets | Authors | Drugs/reagents/treatments | Species | Time points | Main findings | References |
|---|---|---|---|---|---|---|
| Dehydration therapy | Thenuwara et al. | Mannitol, furosemide | Male Sprague-Dawley rats | It was administered intravenously after the baseline measurement of plasma osmolality. | The combination of furosemide with mannitol resulted in a more significant increase in plasma osmolality than seen with mannitol alone and a more significant decrease in brain water at 4 and 8 g/kg of mannitol. | [184] |
| Schreibman et al. | Mannitol and hypertonic saline | Male Wistar rats | First, given 5 hours after ICH induction, then administered every 12 hours thereafter (4 doses total). | Increase in plasma osmolarity one hour after infusion. Reduction in mortality and hemispheric swelling at 48 hours. Inhibition in the activation of microglia/macrophages and the infiltration of CD45+ cells into perihematomal tissues. |
[185] | |
| Deng et al. | Albumin | Adult male Sprague-Dawley rats | Human serum albumin was administered intravenously one hour after ICH. | Improvement in short- and long-term neurobehavioral deficits. Reduced oxidative stress and neuronal death 72 hours after ICH. |
[186] | |
|
| ||||||
| Inhibition of thrombin and RBC hemolysates | Han et al. | EP3R antagonist AE240 | Male C57BL/6 mice | Intraperitoneal injection 20 minutes and 6 hours after striatal thrombin injection and then twice daily for up to 72 hours. | EP3R inhibition mitigated the volume of thrombin-induced brain injury, brain edema, and neurologic deficits. | [32] |
| Ye et al. | NA | NA | NA | Thrombin increased blood-brain barrier disruption and brain edema by mediating PAR (PAR-1, PAR-3, and PAR-4) and their downstream signaling. | [37] | |
| Puech et al. | Dabigatran, rivaroxaban, apixaban, warfarin, and heparin | HBEC-5i human brain endothelial cells | Cells were incubated with or without dabigatran, rivaroxaban, apixaban, warfarin and heparin for 24 hours. The cells were then treated with or without thrombin to mimic a hemorrhagic event for one hour. | Dabigatran treatment allowed the tightness of the endothelial monolayer. Other DOACs limited thrombin-induced alteration of the endothelial monolayer. Pretreatment with warfarin and heparin did not protect against thrombin-induced BBB breakdown. DOACs appear to limit the alteration of BBB in the monolayer of endothelial cells mediated by the thrombin/PAR-1 pathway. |
[187] | |
| Wu et al. | 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA) | Mouse BV2 microglial and N2A cell lines and C57BL/6 mice. | BV2 microglia were incubated with LPS, thrombin, or hemin in the absence or presence of AUDA for 24 hours. AUDA was administered by intracerebroventricular injection 30 min before ICH. |
Reduction in thrombin- and hemin-induced microglial activation in vitro. Alleviation in BBB disruption and MMP-9 activity on day 1 after acute ICH in vivo. |
[188] | |
| Caliaperumal et al. | Bipyridine | Male Sprague-Dawley rats | ip, 20 mg/kg beginning 6 h post-ICH and then every 24 h for 2 days. | Posttreatment with bipyridine had no impact on nonheme parenchymal iron levels, behavioral impairments, or edema after collagenase-induced ICH. Bipyridine did not reduce tissue loss, cell death, or behavioral impairment in the whole-blood ICH model. | [189] | |
| Warkentin et al. | Deferoxamine | Male Sprague-Dawley rats | Intraperitoneal administration of DFX at 0 and 6 hours after ICH. | Treatment with DFX treatment does not influence brain edema or functional recovery after ICH. | [190] | |
| Wu et al. | Deferoxamine (DFX) | C57BL/6 male mice | ip, 6 hours after ICH and then every 12 hours for three days. | DFX did not reduce the volume, edema, or swelling of brain injuries, but improved neurologic function in mice with ICH. | [191] | |
| Li et al. | VK-28 and deferoxamine (DFX) | C57BL/6 mice | Intraperitoneal administration of VK-28 six hours after ICH and then every 12 hours for one, three, or seven consecutive days. | VK-28 polarized microglia to an M2-like phenotype, reduced brain water content, decreased white matter injury, improved neurologic function, and reduced overall death rate after ICH. | [101] | |
| Wu et al. | 2,2′-Dipyridyl, a lipid-soluble ferrous iron chelator | Male C57BL/6 mice | ip, two hours before collagenase injection or six hours after collagenase or blood injection, and then once daily for 1 or 3 days. | Posttreatment with 2,2′-dipyridyl reduced the volume and edema of the brain injury and improved neurologic function. | [192] | |
| Zhu et al. | Deferoxamine mesylate- (DFO-) loaded thermosensitive keratin hydrogels (TKG) | Male Sprague-Dawley rats | DFO loaded TKG-3 (20 μL) was injected with a 26 gauge needle into the hematoma core six hours after ICH. | Reduction in ICH-induced iron deposits, brain nonheme iron content, brain edema, and ROS level. | [69] | |
| Wang et al. | Monascin (a novel natural Nrf2 activator with PPARγ agonist) | Adult male Sprague-Dawley rats | Intragastrical administration of monascin six hours after ICH and twice a day until the euthanasia point. | Alleviation in BBB permeability, edema, and volume of the hematoma. | [71] | |
| Li et al. | IL-10 or CD36-deficient mice | C57BL/6 male mice, IL-10−/− mice, CD36−/− mice | IL-10 or CD36-deficient mice. | IL-10 accelerated hematoma clearance, alleviated brain water content, and promoted functional recovery as long as CD36 expression was intact. | [57] | |
|
| ||||||
| Inhibition or modulation of the inflammatory response | Lin et al. | Heme | C57BL/6, mice, TLR4−/− mice | Injection into the striatum. | TLR4−/− mice showed reduced cerebral edema and lower neurological deficit scores. | [194] |
| Lai et al. | Verbascoside | Male C57BL/6 mice | Intraperitoneal injection of verbascoside at 15 minutes post-ICH. | Improvement in the behavioral score. Reduction in hematoma volume, brain edema, and neuronal apoptosis by targeting TLR4 in a murine model of acute ICH. |
[195] | |
| Wang et al. | TAK-242 | C57BL/6 male mice | Intraperitoneal administration of TAK-242 6 hours after ICH once daily for 5 days. | Reduction in brain water content, neurological deficit scores, and levels of inflammatory factors. | [196] | |
| Masada et al. | Interleukin-1 receptor antagonist | Male Sprague-Dawley rats | Lateral ventricle injection of ten microliters of adenoviral suspension containing 1012 particles/mL immediately after ICH or thrombin injection. | Reduction of polymorphonuclear leukocyte (PMNL) infiltration and brain water content. | [197] | |
| Rynkowski et al. | C3aRA | Adult male C57BL/6J mice | Intraperitoneal administration of C3aRA 45 minutes before ICH or 6 and 12 hours after ICH, followed in both cohorts by doses twice daily for 72 hours. | Improvement in the neurologic outcome. Reduction in infiltration of inflammatory cells and formation of brain edema. |
[198] | |
| Garrett et al. | C5aRA and C3aRA | Adult male C57BL/6J mice | Intraperitoneal administration of C5aRA and C3aRA 6 and 12 hours after ICH, followed by doses twice daily for 72 hours. | Reduction in brain edema and alleviation of neurologic deficits. | [199] | |
| Jing et al. | CD47 blocking antibody | Male and female C57BL/6 mice. | Injection of anti-CD47 antibody in 30 μL blood plus 5 μL clodronate or control liposome into the striatum. | Increase in hematoma/iron clearance by macrophages/microglia. Reduction in ICH-induced brain swelling, neuronal loss, and neurological deficits. |
[104] | |
| Rolland et al. | Fingolimod (FTY-720) | Eight-week-old CD-1 mice | Intraperitoneal administration of FTY720 one hour after ICH. | Reduction in brain edema. Improvement in neurological function at all time points tested. |
[200] | |
| Bobinger et al. | Siponimod (BAF-312) | Adult male C57BL/6 mice | Intraperitoneal administration of BAF-312 30 minutes, 24 hours, and 48 hours after ICH. | Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in the experimental ICH model. | [107] | |
| Bobinger et al. | Siponimod | C57BL/6N mice | A single (30-minute post-ICH) or multiple (three times: 30 minutes, 24 and 48 hours post-ICH) siponimod administration. | Attenuation in the development of brain edema decreased in ICH-induced ventriculomegaly. Improvement in neurological functions. |
[201] | |
| Xu et al. | CAY10444 (S1PR3 antagonist) | Adult male Sprague-Dawley rats | Administration at 6 hours after ICH and every 24 hours beginning on the second day after ICH. | Modulation of S1PR3 can maintain the integrity of BBB integrity by inhibiting the S1PR3/CCL2 axis after ICH. | [202] | |
| Wang et al. | Minocycline | Adult male Sprague–Dawley rats | Intraperitoneal administration immediately and 12 hours after ICH, followed by twice a day for two days. | Improvement in the consequences of ICH by preserving the integrity of the BBB. Attenuating neurologic deficits in a manner related to DKK1 involves enhancing Wnt1-β-catenin activity. |
[36] | |
| Yang et al. | Minocycline | Male piglets | Intramuscular administration 2 hours after ICH and every 12 hours for 3 days. | Reduction in ICH-induced brain swelling, fewer neurological deficits, and fewer white matter injuries. | [205] | |
|
| ||||||
| Other therapy | Kim et al. | Pioglitazone | C57 BL/6 mice | Intraperitoneal administration days 1, 3, and 6 after ICH. | Decrease in NLRP3-related brain edema. | [206] |
| Wu et al. | Rosiglitazone | Male C57/BL mice | Intraperitoneal administration on days 1, 3, and 6 days after ICH. | Increase in PPARγ, decrease in glutamate, BBB permeability, and neurologic deficit scores. | [207] | |
| Guo et al. | Nicardipine hydrochloride entrapped in chitosan nanoparticles | Adult male Sprague-Dawley rats | Intranasal administration immediately following ICH. | Reduction in brain water content. | [208] | |
| Gu et al. | Simvastatin | CD-1 mice | Intragastric administration once a day immediately following ICH. | Reduction in brain edema and cellular apoptosis. Suppression in the NF-κB-mediated MyD88/TRIF signaling pathway. |
[209] | |
| Jiang et al. | Glibenclamide | Sprague-Dawley rats | Glibenclamide was administered intraperitoneally in a single loading dose (10 μg/kg) plus continuous subcutaneous infusion (200 ng/h). | Glibenclamide improved ICH-induced neuroinflammation and improved neurological outcomes in aged rats. | [210] | |
| Kung et al. and Wilkinson et al. | Glibenclamide | Sprague-Dawley rats | Glibenclamide was administered intraperitoneally in a single loading dose (10 μg/kg) plus continuous subcutaneous infusion (200 ng/h). | Glibenclamide has no influence on hematoma volume, brain water content, and functional impairment in mice with ICH. | [211, 212] | |
| Wilkinson et al. | Bumetanide, a specific NKCC1 antagonist | Sprague-Dawley rats | Bumetanide ranged from 10 mg/kg to 40 mg/kg was administered orally at 2 hours or 7 days post-ICH. | Bumetanide did not consistently reduce edema, although there was some indication that it may have modest effects after ICH. | [213] | |
| Li et al. | Neuroserpin | C57BL/6J male mice | Stereotactic injection into the shallow cortex of the hematoma immediately after ICH. | Reduction in brain edema and BBB permeability. Amelioration of neurological deficits. |
[214] | |
| Zhang et al. | Adipose-derived mesenchymal stromal cells (ADSC) | Sprague-Dawley rats | Stereotactic injection into the hemorrhagic brain 48 hours after ICH. | Alleviation in nervous tissue injury and reduction in cell apoptosis. Alleviating brain edema and inhibiting inflammation and expression of the AQP4 protein. |
[215] | |
| Cui et al. | rTMS | C57BL/6J male mice | rTMS was performed every 24 hours for 5 days. | Alleviation of brain edema and functional neural deficits. | [216] | |
| Baker et al. | Therapeutic hypothermia | NA | The cooling strategies employed in the preclinical studies were highly diverse. | Most studies in ICH animals have shown a significant benefit in behavioral scores, cerebral edema, and the blood-brain barrier. Its usage warrants further exploration. | [140] | |
Abbreviations: ICH: intracerebral hemorrhage; PAR: protease activated receptors; BBB: blood-brain barrier; DOC: direct oral anticoagulants; S1PR3: sphingosine-1-phosphate receptor 3; DKK-1: dickkopf1; TLR-4: Toll-like receptor 4; CCL2: monocyte chemotactic protein; NF-κB: nuclear factor kappa-B; MyD88: myeloid differentiation factor88; TRIF: adaptor-inducing interferon-β; PPARγ: peroxisome proliferator-activated receptor γ; AQP-4: aquaporin 4; NLRP3: nucleotide-binding oligomerization domain-like receptor family pyrin domain protein 3; rTMS: repetitive transcranial magnetic stimulation.