Anti-CD47 antibody administration via cisterna magna in proper dosage can reduce perihematomal cell death following intracerebral hemorrhage in rats

Introduction: Intracerebral hemorrhage (ICH) is a type of stroke caused by the loss of vascular integrity leading to bleeding within the brain tissue. Hematoma-derived factors cause secondary injury mechanisms such as cell death days to weeks after the event and in regions distant from the primary insult. Increasing evidence suggests that hemoglobin released by the hematoma is one of the major contributors to neuronal injury in ICH. To date, it is unclear whether brain endothelial cells (EC) are similarly vulnerable to hemolysis products and undergo regulated cell death. Hypothesis: We hypothesized that brain EC undergo multiple, different modes of cell death after ICH and that the underlying mechanisms are different compared to neurons. Methods: We systematically investigated cell death mechanisms in brain EC after exposure to the hemolysis product hemin. We used chemical inhibitors of apoptosis, autophagy, ferroptosis, necroptosis, and parthanatos and assessed biochemical markers of these cell death modes. Results: Brain EC viability was concentration-dependently decreased, starting at higher hemin concentrations than neurons. Treatment of EC with ferroptosis inhibitors protective against hemin toxicity in neurons and against ICH in vivo showed that only N-acetylcysteine and deferoxamine protected brain EC, while ferrostatin-1 and U0126 did not abrogate EC death. The autophagy inhibitor bafilomycin A1 also reduced EC death and hemin increased the expression of the autophagy marker LC3. While inhibitors against apoptosis and parthanatos were not effective, the necroptosis inhibitor GSK872 demonstrated a partial protective effect. Conclusions: Our data suggest that ICH induces different mechanisms of death in EC (ferroptosis and autophagy) compared to neurons (ferroptosis and necroptosis) and may thus warrant a combinatorial therapeutic approach. Further investigations in human and ovine ICH brain tissue are ongoing.

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AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage

BioMed Research International ◽

10.1155/2018/3706047 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Xiao Lin ◽

Haotuo Ye ◽

Felix Siaw-Debrah ◽

Sishi Pan ◽

Zibin He ◽

...

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Cell Damage ◽

Neuronal Cell ◽

Neurological Function ◽

Inflammatory Factors ◽

Neuroprotective Effects ◽

Caspase 1 ◽

Cell Death Pathways ◽

Cell Death Pathway

Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

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Excitatory and Mitogenic Signaling in Cell Death, Blood–brain Barrier Breakdown, and BBB Repair after Intracerebral Hemorrhage

Translational Stroke Research ◽

10.1007/s12975-012-0147-z ◽

2012 ◽

Vol 3 (S1) ◽

pp. 62-69 ◽

Cited By ~ 11

Author(s):

Da-Zhi Liu ◽

Frank R. Sharp

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Mitogenic Signaling ◽

Blood Brain ◽

Barrier Breakdown ◽

Blood Brain Barrier Breakdown

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Celecoxib Induces Functional Recovery after Intracerebral Hemorrhage with Reduction of Brain Edema and Perihematomal Cell Death

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000130866.25040.7d ◽

2004 ◽

Vol 24 (8) ◽

pp. 926-933 ◽

Cited By ~ 125

Author(s):

Kon Chu ◽

Sang-Wuk Jeong ◽

Keun-Hwa Jung ◽

So-Young Han ◽

Soon-Tae Lee ◽

...

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Brain Edema ◽

Functional Recovery ◽

Autologous Blood ◽

Prostaglandin E ◽

Dependent Manner ◽

Behavioral Tests ◽

Adult Rats ◽

Cox 2

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

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