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.

following correction should be noted. In Fig. 1b, the designed sequence of amino acids S 36 contains a typographical error in that only 35 of its 36 monomers appear. The missing amino acid is of type R and should be located between amino acids E (sixth) and G (seventh). The correct sequence is:Although this typographical error does not change the results presented in the paper because they were obtained with the correct number and sequence of amino acids, it constitutes a nuisance for anybody interested in reproducing our results, and we apologize for the inconvenience. We want to thank Prof. H. S. Chan, of the University of Toronto, for calling our attention to this error.Cell Biology. In the article "Quantitative analysis of biological membrane lipids at the low picomole level by nanoelectrospray ionization tandem mass spectrometry" by B. Brügger, G. Erben, R. Sandhoff, F. T. Wieland, and W. D.Lehmann, which appeared in number 6, March 18, 1997, of Proc. Natl. Acad. Sci. USA (94,(2339)(2340)(2341)(2342)(2343)(2344), Table 1 Medical Sciences. In the article "Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption" by Hiroyuki Yoshitake, Susan R. Rittling, David T. Denhardt, and Masaki Noda, which appeared in number 14, July, 1999, of Proc. Natl. Acad. Sci. USA (96,(8156)(8157)(8158)(8159)(8160), the authors request the following correction. In the 9th line in the first paragraph and in Table 3 Figs. 1 and 2. Its true placement is Ϸ40 kilobase pairs further centromeric at base pairs 162581 to 162673 of GenBank submission AF152363. Thus, the length of intron 4 is 284935 base pairs and the markers D3S4489 and D3S4260 and the proximal aphidicolin-induced hybrid breaks are telomeric to exon 4, i.e., in intron 4.Microbiology. In the article "A set of independent selectable markers for transfection of the human malaria parasite Plasmodium falciparum" by Choukri Ben Mamoun, Ilya Y. Gluzman, Sophie Goyard, Stephen M. Beverley, and Daniel E. Goldberg, which appeared in number 15, July 20, 1999, of Proc. Natl. Acad. Sci. USA (96,(8716)(8717)(8718)(8719)(8720), the authors request the following corrections. In Experimental Procedures (page 8717), under "P. falciparum Transfection and Selection of Transfectants," there was a typographical error in the concentrations of G418 used for selection. The correct concentrations are 300, 500, or 1,000 g/ml. Under "BSD Enzyme Assay," there was a typographical error in the volume of cultured parasitized red blood cells used. The correct volume is 12 ml. In Results (page 8718, line 24 in column 2), the sentence should read: "Varying amounts of either gene were slotted onto the blot, corresponding to the amount of DNA that would be present per microgram of total DNA if there were 1-35 copies of the construct per cell." Neurobiology. In the article "Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury" by Sylvain Doré, Masaaki Takahashi, Christopher D. Ferris, Lynda D. Hester, Daniel Guastella, and Solomon H. Snyde...

Haem oxygenase-1 (HO1) is a heat-shock protein that is induced by stressful stimuli. Here we demonstrate a cytoprotective role for HO1: cell death produced by serum deprivation, staurosporine or etoposide is markedly accentuated in cells from mice with a targeted deletion of the HO1 gene, and greatly reduced in cells that overexpress HO1. Iron efflux from cells is augmented by HO1 transfection and reduced in HO1-deficient fibroblasts. Iron accumulation in HO1-deficient cells explains their death: iron chelators protect HO1-deficient fibroblasts from cell death. Thus, cytoprotection by HO1 is attributable to its augmentation of iron efflux, reflecting a role for HO1 in modulating intracellular iron levels and regulating cell viability.

As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.

Because heme oxygenase (HO) is the rate limiting enzyme in the degradation of the pro-oxidant hemin/heme from blood, here we investigated the contribution of the inducible HO-1 to early brain injury produced by intracerebral haemorrhage (ICH). We found that after induction of ICH, HO-1 proteins were highly detectable in the peri-ICH region predominantly in microglia/macrophages and endothelial cells. Remarkably, the injury volume was significantly smaller in HO-1 knockout (HO-1-/-) mice than in wild-type controls 24 and 72 h after ICH. Although the brain water content did not appear to be significantly different, the protection in HO-1-/- mice was associated with a marked reduction in ICH-induced leucocyte infiltration, microglia/macrophage activation and free radical levels. These data reveal a previously unrecognized role of HO-1 in early brain injury after ICH. Thus, modulation of HO-1 signalling should be assessed further in clinical settings, especially for haemorrhagic states.

Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well-defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 microg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre-exposure to Abeta25-35 and Abeta1-40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50-150 microM), a major peroxide possibly involved in mediating Abeta toxicity. Moreover, EGb 761 (10-100 microg/mL), and to a lesser extent CP 205 (10-50 microg/mL), completely blocked Abeta-induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Abeta-induced toxicity and cell death.

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Nrf2 is a key transcriptional factor for antioxidant response element (ARE)-regulated genes. While its beneficial role has been described for stroke, its contribution to intracerebral hemorrhage (ICH)-induced early brain injury remains to be determined. Using wildtype (WT) and Nrf2 knockout (Nrf2 −/− ) mice, the role of Nrf2 in ICH induced by intracerebral injection of collagenase was investigated. The results showed that injury volume was significantly larger in Nrf2 −/− mice than in WT controls 24 h after induction of ICH (p < 0.05), an outcome that correlated with neurological deficits. This exacerbation of brain injury in Nrf2 −/− mice was also associated with an increase in leukocyte infiltration, production of reactive oxygen species, DNA damage, and cytochrome c release during the critical early phase of the post-ICH period. In combination, these results suggest that Nrf2 reduces ICH-induced early brain injury, possibly by providing protection against leukocyte-mediated free radical oxidative damage.