Aldehyde load in ischemia–reperfusion brain injury: Neuroprotection by neutralization of reactive aldehydes with phenelzine

Wood, Paul L.; Khan, M. Amin; Moskal, Joseph R.; Todd, Kathryn G.; Tanay, Véronique A.-M. I.; Baker, Glen B.

doi:10.1016/j.brainres.2006.09.003

Cited by 81 publications

(81 citation statements)

References 46 publications

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“…In addition to H 2 O 2 , SMO produces 3-aminopropanal, a byproduct that contributes to the formation of acrolein, a highly reactive aldehyde. Acrolein associated with elevated polyamine catabolism has been strongly implicated in the etiology of diseases including ischemia-reperfusion injuries, renal failure, stroke, and silent brain infarction (39)(40)(41)(42)(43)(44). Further, elevated SMO expression has been observed in inflammation-associated human diseases including gastritis (22), ulcerative colitis (23), and prostatic intraepithelial neoplasia (24).…”

Section: Resultsmentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

490

353

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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Section: Resultsmentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

490

353

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“…10 While the molecular mechanisms of 4-HNE mitochondrial toxicity still remain unclear, it has been observed demonstrated that the generation of additional ROS and additional LP initiation is involved in the mechanism(s) of 4-HNE-induced neurotoxicity. 26,27 Whatever the intricacies of 4-HNE neurotoxicity are, the loss of mitochondrial integrity is the pivotal event leading to neuronal cell death in the ischemic penumbra in stroke models 13 and in models of acute neurological injury including TBI 1,28 and spinal cord injury. 29,30 Our in vitro data demonstrate protective effects of PZ against 4-HNE-induced bioenergetic function and oxidative damage in isolated mitochondria that tracks with a decrease in 4-HNE modification of mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 99%

“…However, PZ has been shown by others to attenuate acrolein toxicity in cultured retinal ganglion cells by sequestration of acrolein. 13 This effect of PZ caused us to investigate whether PZ could similarly protect against early mitochondrial failure during the first 3 hours after TBI. As shown, a single subcutaneous dose of PZ at 15 minutes after TBI significantly reduced the degree of post-TBI S h a m V e h i c l e P h e n e l z i n e S h a m V e h i c l e P h e n e l z i n e S h a m V e h i c l e P h e n e l z i n e respiratory compromise, and this effect appears to be related to a decrease in 4-HNE modified mitochondrial proteins in the contusion and immediate peri-contusion area (the latter data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Phenelzine Mitochondrial Functional Preservation and Neuroprotection after Traumatic Brain Injury Related to Scavenging of the Lipid Peroxidation-Derived Aldehyde 4-Hydroxy-2-Nonenal

Singh

Gilmer

Miller

et al. 2013

J Cereb Blood Flow Metab

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Phenelzine (PZ) is a scavenger of the lipid peroxidation (LP)-derived reactive aldehyde 4-hydroxynonenal (4-HNE) due to its hydrazine functional group, which can covalently react with 4-HNE. In this study, we first examined the ability of PZ to prevent the respiratory depressant effects of 4-HNE on normal isolated brain cortical mitochondria. Second, in rats subjected to controlled cortical impact traumatic brain injury (CCI-TBI), we evaluated PZ (10 mg/kg subcutaneously at 15 minutes after CCI-TBI) to attenuate 3-hour post-TBI mitochondrial respiratory dysfunction, and in separate animals, to improve cortical tissue sparing at 14 days. While 4-HNE exposure inhibited mitochondrial complex I and II respiration in a concentration-dependent manner, pretreatment with equimolar concentrations of PZ antagonized these effects. Western blot analysis demonstrated a PZ decrease in 4-HNE in mitochondrial proteins. Mitochondria isolated from peri-contusional brain tissue of CCI-TBI rats treated with vehicle at 15 minutes after injury showed a 37% decrease in the respiratory control ratio (RCR) relative to noninjured mitochondria. In PZ-treated rats, RCR suppression was prevented (Po0.05 versus vehicle). In another cohort, PZ administration increased spared cortical tissue from 86% to 97% (Po0.03). These results suggest that PZ's neuroprotective effect is due to mitochondrial protection by scavenging of LP-derived 4-HNE.

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“…Seeking to offset such damage, researchers have explored the use of nucleophilic drugs to scavenge "free" carbonyls within cells, attempting to attenuate macromolecular adduction and any accompanying toxicity (Aldini et al, 2007(Aldini et al, , 2011aBurcham, 2008). Agents that have attracted attention as "carbonyl scavengers" include the neuroprotectant evaradone (Aldini et al, 2010), the antidepressant phenelzine (Wood et al, 2006), the hypoglycemic metformin (Ruggiero-Lopez et al, 1999), the antimicrobial isoniazid (Galvani et al, 2008), the dipeptide carnosine (Aldini et al, 2011b), the vasodilator hydralazine , the antioxidant ascorbate (Kesinger et al, 2010), and various biogenic polyphenolic compounds (Zhu et al, 2009). For some of these agents, interpreting their in vivo efficacy is complicated by "secondary" pharmacological actions unrelated to carbonyl-sequestering reactivity; hence, further medicinal chemistry workup may be needed to derive useful "pharmacologically inert" carbonyl scavengers Bouguerne et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

Burcham

Raso²,

Kaminskas

2012

Mol Pharmacol

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Toxic carbonyls such as acrolein participate in many degenerative diseases. Although the nucleophilic vasodilatory drug hydralazine readily traps such species under "test-tube" conditions, whether these reactions adequately explain its efficacy in animal models of carbonyl-mediated disease is uncertain. We have previously shown that hydralazine attacks carbonyl-adducted proteins in an "adduct-trapping" reaction that appears to take precedence over direct "carbonyl-sequestering" reactions, but how this reaction conferred cytoprotection was unclear. This study explored the possibility that by increasing the bulkiness of acrolein-adducted proteins, adduct-trapping might alter the redistribution of chaperones to damaged cytoskeletal proteins that are known targets for acrolein. Using A549 lung adenocarcinoma cells, the levels of chaperones heat shock protein (Hsp) 40, Hsp70, Hsp90, and Hsp110 were measured in intermediate filament extracts prepared after a 3-h exposure to acrolein. Exposure to acrolein alone modestly increased the levels of all four chaperones. Coexposure to hydralazine (10 -100 M) strongly suppressed cell ATP loss while producing strong adduct-trapping in intermediate filaments. Most strikingly, hydralazine selectively boosted the levels of cytoskeletal-associated Hsp90, including a high-mass species that was sensitive to the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin. Biochemical fractionation of acrolein-and hydralazine-treated cells revealed that hydralazine likely promoted Hsp90 migration from cytosol into other subcellular compartments. A role for Hsp90 mobilization in cytoprotection was confirmed by the finding that brief heat shock treatment suppressed acute acrolein toxicity in A549 cells. Taken together, these findings suggest that by increasing the steric bulk of carbonyl-adducted proteins, adduct-trapping drugs trigger the intracellular mobilization of the key molecular chaperone Hsp90.

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Aldehyde load in ischemia–reperfusion brain injury: Neuroprotection by neutralization of reactive aldehydes with phenelzine

Cited by 81 publications

References 46 publications

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Phenelzine Mitochondrial Functional Preservation and Neuroprotection after Traumatic Brain Injury Related to Scavenging of the Lipid Peroxidation-Derived Aldehyde 4-Hydroxy-2-Nonenal

Chaperone Heat Shock Protein 90 Mobilization and Hydralazine Cytoprotection against Acrolein-Induced Carbonyl Stress

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