This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

Pharmacological and Clinical Aspects of Heme Oxygenase

The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of t...

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Blood-Brain Barrier: From Physiology to Disease and Back

Summary Intracerebral haemorrhage accounts for about 10–15% of all strokes and is associated with high mortality and morbidity. No successful phase 3 clinical trials for this disorder have been completed. In the past 6 years, the number of preclinical and clinical studies focused on intracerebral haemorrhage has risen. Important advances have been made in animal models of this disorder and in our understanding of mechanisms underlying brain injury after haemorrhage. Several therapeutic targets have subsequently been identified that are now being pursued in clinical trials. Many clinical trials have been based on limited preclinical data, and guidelines to justify taking preclinical results to the clinic are needed.

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Intracerebral haemorrhage: mechanisms of injury and therapeutic targets

Intracerebral hemorrhage (ICH) is an often fatal type of stroke that kills ≈30 000 people annually in the United States. If the patient survives the ictus, then the resulting hematoma within brain parenchyma triggers a series of adverse events causing secondary insults and severe neurological deficits. This article discusses selected aspects of secondary brain injury after ICH and outlines key mechanisms associated with hematoma toxicity, oxidative stress, and inflammation. Finally, this review discusses the relevance of hematoma resolution processes as a target for ICH therapy and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with ICH injury.

Molecular Pathophysiology of Cerebral Hemorrhage Secondary Brain Injury

Intracerebral hemorrhage (ICH) is a devastating clinical event without effective therapies. Increasing evidence suggests that inflammatory mechanisms are involved in the progression of ICH-induced brain injury. Inflammation is mediated by cellular components, such as leukocytes and microglia, and molecular components, including prostaglandins, chemokines, cytokines, extracellular proteases, and reactive oxygen species. Better understanding of the role of the ICH-induced inflammatory response and its potential for modulation might have profound implications for patient treatment. In this review, a summary of the available literature on the inflammatory responses after ICH is presented along with discussion of some of the emerging opportunities for potential therapeutic strategies. In the near future, additional strategies that target inflammation could offer exciting new promise in the therapeutic approach to ICH.

https://journals.sagepub.com/doi/pdf/10.1038/sj.jcbfm.9600403

Inflammation after Intracerebral Hemorrhage

In this paper, we review current knowledge on blood-brain barrier (BBB) dysfunction following intracerebral hemorrhage (ICH). BBB disruption is a hallmark of ICH-induced brain injury. Such disruption contributes to edema formation, the influx of leukocytes, and the entry of potentially neuroactive agents into the perihematomal brain, all of which may contribute to brain injury. A range of factors have been implicated in inducing BBB disruption, including inflammatory mediators (e.g., cytokines and chemokines), thrombin, hemoglobin breakdown products, oxidative stress, complement, and matrix metalloproteinases. While there is interaction between some of these mediators, it is probable that prevention of ICH-induced BBB disruption will involve blocking multiple pathways or blocking a common end pathway (e.g., by stabilizing tight junction structure). While the effects of ICH on BBB passive permeability have been extensively examined, effects on other ‘barrier’ properties (metabolic and transport functions) have been less well-studied. However, recent data suggests that ICH can affect transport and that this may help protect the BBB and the brain. Indeed, it is possible in small bleeds that BBB disruption may be beneficial, and it is only in the presence of larger bleeds that disruption has detrimental effects.

Blood-brain barrier function in intracerebral hemorrhage.

Microglial activation and thrombin formation contribute to brain injury after intracerebral hemorrhage (ICH). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) are 2 major proinflammatory cytokines. In this study, we investigated whether thrombin stimulates TNF-alpha and IL-1beta secretion in vitro, and whether microglial inhibition reduces ICH-induced brain injury in vivo. There were 2 parts to this study. In the first part, cultured rat microglial cells were treated with vehicle, thrombin (5 and 10U/mL), or thrombin plus tuftsin (0.05 microg/mL), an inhibitor of microglia activation. Levels of TNF-alpha and IL-1beta in culture medium were measured by ELISA at 4, 8, and 24 h after thrombin treatment. In the second part of the study, rats received an intracerebral infusion of 100 microL autologous whole blood with or without 25 microg of tuftsin 1-3 fragment. Rats were killed at day 1 or day 3 for immunohistochemistry and brain water content measurement. We found that thrombin receptors were expressed in cultured microglia cells, and TNF-alpha and IL-1beta levels in the culture medium were increased after thrombin treatment. Tuftsin reduced thrombin-induced upregulation of TNF-alpha and IL-1beta. In vivo, microglia were activated after ICH, and intracerebral injection of tuftsin reduced brain edema in the ipsilateral basal ganglia (81.1 +/- 0.7% vs. 82.7 +/- 1.3% in vehicle-treated group; p < 0.05) after ICH. These results suggest a critical role of microglia activation in ICH-related brain injury.

Microglial activation and brain injury after intracerebral hemorrhage.

We investigated the occurrence of DNA damage in brain after intracerebral hemorrhage (ICH) and the role of iron in such injury.

Iron-induced oxidative brain injury after experimental intracerebral hemorrhage.

Iron overload occurs in brain after intracerebral hemorrhage (ICH). Deferoxamine, an iron chelator, attenuates perihematomal edema and oxidative stress in brain after ICH. We investigated the effects of deferoxamine on cerebrospinal fluid (CSF) free iron and brain total iron following ICH.

Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage

Hemoglobin degradation products result in brain injury after intracerebral hemorrhage (ICH). Recent studies found that intracerebral infusion of heme oxygenase inhibitors reduces hemoglobin- and ICH-induced brain edema in rats and pigs. The present study examined whether systemic use of zinc protoporphyrin (ZnPP), a heme oxygenase inhibitor, can attenuate brain edema, behavioral deficits, and brain atrophy following ICH.

G. Xi

Papers

Blood-brain barrier function in intracerebral hemorrhage.

Microglial activation and brain injury after intracerebral hemorrhage.

Iron-induced oxidative brain injury after experimental intracerebral hemorrhage.

Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage

Systemic zinc protoporphyrin administration reduces intracerebral hemorrhage-induced brain injury.