Christopher D. Aluise

2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain.

Doxorubicin (DOX), an anthracycline used to treat a variety of cancers, is known to generate intracellular reactive oxygen species. Moreover, many patients who have undergone chemotherapy complain of cognitive dysfunction often lasting years after cessation of the chemotherapy. Previously, we reported that intraperitoneal administration of DOX led to elevated TNF-α and oxidative stress in the plasma and brain of mice. However, the mechanisms involved in nontargeted tissue damage remain unknown. In this study, we measured plasma oxidative stress and cytokine levels in patients treated with DOX. We observed increased plasma protein carbonylation and elevation of TNF-α 6 h after DOX administration in the context of multiagent chemotherapy regimens. Importantly, patients not treated coincidentally with 2-mercaptoethane sulfonate (MESNA) showed statistically significantly increased plasma protein-bound 4-hydroxynonenal, whereas those who had been coincidentally treated with MESNA as part of their multiagent chemotherapy regimen did not, suggesting that concomitant administration of the antioxidant MESNA with DOX prevents intravascular oxidative stress. We demonstrate in a murine model that MESNA suppressed DOX-induced increased plasma oxidative stress indexed by protein carbonyls and protein-bound HNE, and also suppressed DOX-induced increased peripheral TNF-α levels. A direct interaction between DOX and MESNA was demonstrated by MESNA suppression of DOX-induced DCF fluorescence. Using redox proteomics, we identified apolipoprotein A1 (APOA1) in both patients and mice after DOX administration as having increased specific carbonyl levels. Macrophage stimulation studies showed that oxidized APOA1 increased TNF-α levels and augmented TNF-α release by lipopolysaccharide, effects that were prevented by MESNA. This study is the first to demonstrate that DOX oxidizes plasma APOA1, that oxidized APOA1 enhances macrophage TNF-α release and thus could contribute to potential subsequent TNF-α-mediated toxicity, and that MESNA interacts with DOX to block this mechanism and suggests that MESNA could reduce systemic side effects of DOX.

Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: Implications for Aβ accumulation in AD brain

Alzheimer disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SPs), neurofibrillary tangles, and synapse loss. The main component of SPs is amyloid-β peptide (Aβ), which has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier. Impaired brain-to-blood transport of Aβ by LRP1 has been hypothesized to contribute to increased levels of Aβ in AD brain. The cause of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1, thus damaging its own transporter. Consistent with this notion, we report in this study a significant increase in the levels of the lipid peroxidation product 4-hydroxy-2-nonenal bound to transmembrane LRP1 in AD hippocampus. In contrast, the levels of LRP1-resident 3-nitrotyrosine did not show a significant increase in AD hippocampus compared to age-matched controls. Based on this study, we propose that Aβ impairs its own efflux from the brain by oxidation of its transporter LRP1, leading to increased Aβ deposition in brain, thereby contributing to subsequent cognitive impairment in AD.

Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease

Alzheimers disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed. Biomarkers are multidimensional and have the potential to aid in various facets of AD such as diagnostic prediction, assessment of disease stage, discrimination from normally cognitive controls as well as other forms of dementia, and therapeutic efficacy of AD drugs. To date, biomarker research has focused on plasma and cerebrospinal fluid (CSF), two bodily fluids believed to contain the richest source of biomarkers for AD. CSF is the fluid surrounding the central nervous system (CNS), and is the most indicative obtainable fluid of brain pathology. Blood plasma contains proteins that affect brain processes from the periphery, as well as proteins/peptides exported from the brain; this fluid would be ideal for biomarker discovery due to the ease and non-invasive process of sample collection. However, it seems reasonable that biomarker discovery will result in combinations of CSF, plasma, and other fluids such as urine, to serve the aforementioned purposes. This review focuses on proteins and peptides identified from CSF, plasma, and urine that may serve as biomarkers in AD.

Chemo Brain (Chemo Fog) as a Potential Side Effect of Doxorubicin Administration: Role of Cytokine-Induced, Oxidative/Nitrosative Stress in Cognitive Dysfunction

Doxorubicin (ADRIAMYCIN, RUBEX) is a chemotherapeutic agent that is commonly administered to breast cancer patients in standard chemotherapy regimens. As true of all such therapeutic cytotoxic agents, it can damage normal, noncancerous cells and might affect biochemical processes in a manner that might lead to, or contribute to, chemotherapy-induced cognitive deficits when administered either alone or in combination with other agents.

Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: Toward therapeutic modulation of mild cognitive impairment

Alzheimers disease (AD) is the most prevalent form of dementia among the elderly. Although the underlying cause has yet to be established, numerous data have shown that oxidative stress is implicated in AD as well as in preclinical stages of AD, such as mild cognitive impairment (MCI). The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid‐β peptide (Aβ). By using double human mutant APP/PS‐1 knock‐in mice as the AD model, the present work demonstrates that the APP/PS‐1 double mutation results in elevated protein oxidation (as indexed by protein carbonyls), protein nitration (as indexed by 3‐nitrotyrosine), as well as lipid peroxidation (as indexed by protein‐bound 4‐hydroxy‐2‐nonenal) in brains of mice aged 9 months and 12 months. APP/PS‐1 mice also exhibited lower levels of brain glutathione peroxidase (GPx) in both age groups studied, whereas glutathione reductase (GR) levels in brain were unaffected by the mutation. The activities of both of these antioxidant enzymes were significantly decreased in APP/PS‐1 mouse brains, whereas the activity of glucose‐6‐phosphate dehydrogenase (G6PDH) was increased relative to controls in both age groups. Levels of peptidyl prolyl isomerase 1 (Pin1) were significantly decreased in APP/PS‐1 mouse brain aged 9 and 12 months. Administration of N‐acetyl‐L‐cysteine (NAC), a glutathione precursor, to APP/PS‐1 mice via drinking water suppressed increased protein oxidation and nitration and also significantly augmented levels and activity of GPx in brain from both age groups. Oral administration of NAC also increased the diminished activity of GR and protected against lipid peroxidation in brains of 9‐month‐old APP/PS‐1 mice only. Pin1 levels, GR levels, and G6PDH activity in brain were unaffected by oral administration of NAC in both age groups. These results are discussed with reference to the therapeutic potential of this brain‐accessible glutathione precursor in the treatment of MCI and AD.

In vivo amelioration of adriamycin induced oxidative stress in plasma by gamma-glutamylcysteine ethyl ester (GCEE)

Adriamycin (ADR) is a common chemotherapeutic known to generate significant amounts of reactive oxygen species (ROS). Although ROS generation is one of several means by which ADR attacks cancerous tissues, oxidative stress-related toxicity has been documented in several non-targeted organs as a result of anthracycline chemotherapy. Oxidative damage to tissues has been shown in the past to be minimized with co-administration of various antioxidants. Gamma-glutamylcysteine ethyl ester (GCEE) is an antioxidant and precursor to glutathione that has been shown to successfully defend brain against ADR-induced oxidative stress. The current study shows ADR in vivo also causes oxidative stress in plasma in the form of protein oxidation [indexed by protein carbonyls and protein bound 3-nitrotyrosine] and lipid peroxidation [indexed by protein-bound-4-hydroxynonenal]. All three markers of oxidative stress are significantly suppressed with in vivo co-administration of GCEE. This work further supports the concept that administration of GCEE can protect patients undergoing anthracycline chemotherapy from non-targeted oxidative damage.

Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SPs), neurofibrillary tangles, and synapse loss. The main component of SPs is amyloid-β peptide (Aβ), which has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier. Impaired brain-to-blood transport of Aβ by LRP1 has been hypothesized to contribute to increased levels of Aβ in AD brain. The cause of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1, thus damaging its own transporter. Consistent with this notion, we report in this study a significant increase in the levels of the lipid peroxidation product 4-hydroxy-2-nonenal bound to transmembrane LRP1 in AD hippocampus. In contrast, the levels of LRP1-resident 3-nitrotyrosine did not show a significant increase in AD hippocampus compared to age-matched controls. Based on this study, we propose that Aβ impairs its own efflux from the brain by oxidation of its transporter LRP1, leading to increased Aβ deposition in brain, thereby contributing to subsequent cognitive impairment in AD.

Oxidative Modification to LDL-related Receptor Protein 1 (LRP1) in Hippocampus from Subjects with Alzheimer’s Disease: Implications for Aβ Accumulation in AD Brain

Alzheimer disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SPs), neurofibrillary tangles, and synapse loss. The main component of SPs is amyloid-β peptide (Aβ), which has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier. Impaired brain-to-blood transport of Aβ by LRP1 has been hypothesized to contribute to increased levels of Aβ in AD brain. The cause of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1, thus damaging its own transporter. Consistent with this notion, we report in this study a significant increase in the levels of the lipid peroxidation product 4-hydroxy-2-nonenal bound to transmembrane LRP1 in AD hippocampus. In contrast, the levels of LRP1-resident 3-nitrotyrosine did not show a significant increase in AD hippocampus compared to age-matched controls. Based on this study, we propose that Aβ impairs its own efflux from the brain by oxidation of its transporter LRP1, leading to increased Aβ deposition in brain, thereby contributing to subsequent cognitive impairment in AD.