Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

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 10^12 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.