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.
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.
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.
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.
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.
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.
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.
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.
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.
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.