Hemoglobin potentiates central nervous system damage.

The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin. A prior cell culture study demonstrated that deletion of HO-2, the isoform constitutively expressed in neurons, attenuated hemoglobin (Hb) neurotoxicity. The present study tested the hypothesis that HO-2 gene deletion is cytoprotective in a model of Hb toxicity in vivo. Stereotactic injection of 6 lL stroma-free Hb (SFHb) into the striatum significantly increased protein oxidation in wild-type mice at 24 to 72 h, as detected by an assay for carbonyl groups. At 72 h, carbonylation was increased 2.5-fold compared with that in the contralateral striatum. In HO-2 knockout mice, protein oxidation was not increased at 24 h, and was increased by only 1.7-fold at 72 h. Similarly, striatal lipid peroxidation, as detected by the malondialdehyde assay, was significantly greater in the SFHb-injected striata of wild-type mice than in knockout mice. Striatal cell viability, determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was 45.0%76.3% of that in contralateral striata in wild-type mice at 72 h; it was increased to 85%7 8% in knockouts. Heme oxygenase-2 gene deletion did not alter weight loss or mortality after SFHb injection. Baseline striatal HO-1 expression was similar in knockout and wild-type mice; induction after SFHb injection occurred more rapidly in the latter. These results suggest that HO-2 gene deletion protects striatal cells from the oxidative toxicity of Hb in vivo. Pharmacologic or genetic strategies that target HO-2 may be beneficial after central nervous system hemorrhage, and warrant further investigation.

Section: Ho-1 Band Dencitysupporting

confidence: 81%

Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

Chen

Benvenisti-Zarom

et al. 2005

“…The data shown in Figure 6A indicate that the well-known neurotoxic effect of hemoglobin (Regan and Panter, 1993;Sadrzadeh et al, 1987) is related to the heme moiety but not to the globin polypeptide chain. However, astrocytes showed no sensitivity to any of the blood products tested (globin, hemoglobin, hemoglobin-reconstituted globin, or heme) ( Figure 6B).…”

Section: Discussionmentioning

confidence: 94%

“…Hemoglobin is known to be deleterious to the central nervous system, with both neuroexcitatory and neurotoxic effects (Rosen and Frumin, 1979;Sadrzadeh et al, 1987). One obvious mechanism for hemoglobin neurotoxicity is through reactive oxygen species formation (Sadrzadeh and Eaton, 1988), which is related to free heme release from hemoglobin digestion and subsequently of free iron from the breakdown of heme by HO-2 in neurons and/or HO-1 in neuronal and glial cells.…”

Section: More Efficient Hemoglobin Uptake In Neurons Triggers Oxidatimentioning

confidence: 99%

On the Fate of Extracellular Hemoglobin and Heme in Brain

Lara

Kahn

Fonseca

et al. 2009

Intracerebral hemorrhage (ICH) is a major cause of disability in adults worldwide. The pathophysiology of this syndrome is complex, involving both inflammatory and redox components triggered by the extravasation of blood into the cerebral parenchyma. Hemoglobin, heme, and iron released therein seem be important in the brain damage observed in ICH. However, there is a lack of information concerning hemoglobin traffic and metabolism in brain cells. Here, we investigated the fate of hemoglobin and heme in cultured neurons and astrocytes, as well as in the cortex of adult rats. Hemoglobin was made traceable by conjugation to Alexa 488, whereas a fluorescent heme analogue (tin-protoporphyrin IX) was prepared to allow heme tracking. Using fluorescence microscopy we observed that neurons were more efficient in uptake hemoglobin and heme than astrocytes. Exposure of cortical neurons to hemoglobin or heme resulted in an oxidative stress condition. Viability assays showed that neurons were more susceptible to both hemoglobin and heme toxicity than astrocytes. Together, these results show that neurons, rather than astrocytes, preferentially take up hemoglobin-derived products, indicating that these cells are actively involved in the ICH-associated brain damage.

“…As a result of hemorrhage, the extracellular spaces of the brain become exposed to hemoglobin and its breakdown products. Iron and iron-related compounds, including hemoglobin, catalyze hydroxyl radical production and lipid peroxidation (Sadrzadeh et al, 1987;Sadrzadeh and Eaton, 1988), which expose the brain cells to increased levels of oxidative stress. Indeed, high Asterisks indicate a significant increase in activity-positive blood vessels in collagenase-injected mice compared with sham-operated control mice (n = 6/group, *P < 0.001).…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Inflammation after Intracerebral Hemorrhage

Wang

Doré

2007

585

609

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.