Article

AEOL10150: A novel therapeutic for rescue treatment after toxic gas lung injury

Meakins Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H2X 2P2, Canada.
Free Radical Biology and Medicine (Impact Factor: 5.74). 03/2011; 50(5):602-8. DOI: 10.1016/j.freeradbiomed.2010.12.001
Source: PubMed

ABSTRACT

New therapeutics designed as rescue treatments after toxic gas injury such as from chlorine (Cl(2)) are an emerging area of interest. We tested the effects of the metalloporphyrin catalytic antioxidant AEOL10150, a compound that scavenges peroxynitrite, inhibits lipid peroxidation, and has SOD and catalase-like activities, on Cl(2)-induced airway injury. Balb/C mice received 100ppm Cl(2) gas for 5 min. Four groups were studied: Cl(2) only, Cl(2) followed by AEOL10150 1 and 9 h after exposure, AEOL10150 only, and control. Twenty-four hours after Cl(2) gas exposure airway responsiveness to aerosolized methacholine (6.25-50mg/ml) was measured using a small-animal ventilator. Bronchoalveolar lavage (BAL) was performed to assess airway inflammation and protein. Whole lung tissue was assayed for 4-hydroxynonenal. In separate groups, lungs were collected at 72 h after Cl(2) injury to evaluate epithelial cell proliferation. Mice exposed to Cl(2) showed a significantly higher airway resistance compared to control, Cl(2)/AEOL10150, or AEOL10150-only treated animals in response to methacholine challenge. Eosinophils, neutrophils, and macrophages were elevated in BAL of Cl(2)-exposed mice. AEOL10150 attenuated the increases in neutrophils and macrophages. AEOL10150 prevented Cl(2)-induced increase in BAL fluid protein. Chlorine induced an increase in the number of proliferating airway epithelial cells, an effect AEOL10150 attenuated. 4-Hydroxynonenal levels in the lung were increased after Cl(2) and this effect was prevented with AEOL10150. AEOL10150 is an effective rescue treatment for Cl(2)-induced airway hyperresponsiveness, airway inflammation, injury-induced airway epithelial cell regeneration, and oxidative stress.

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    • "Like the endogenous antioxidant superoxide dismutase (SOD), this compound contains an active site metal that catalyzes the dismutation reaction of both superoxide and hydrogen peroxide catalytically, without requiring energy from the cell (Castello et al., 2008). Mn III TDE-2-ImP 5+ has been proven efficacious at reducing oxidative stress in animal models of brain ischemic injury as well as radiation and vesicant-induced lung injury (Sheng et al., 2002; Rabbani et al., 2007; O'Neill et al., 2011; McGovern et al., 2011; Tewari-Singh et al., 2014). In the current study, we verified brain levels of the compound in plasma and hippocampus at concentrations known to exert antioxidant and neuroprotective effects (Sheng et al., 2002; O'Neill et al., 2011). "
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    ABSTRACT: Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, no targeted therapies are available and the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unknown. Oxidative stress is known to occur in the pathogenesis of TLE but its functional role remains to be determined. Here, we demonstrate that oxidative stress and resultant processes contribute to cognitive decline associated with epileptogenesis. Using a synthetic catalytic antioxidant, we show that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus (SE) or epilepsy development in a rat model of SE-induced TLE. Moreover, the effects of the catalytic antioxidant on cognition persisted beyond the treatment period suggestive of disease-modification. The data implicate oxidative stress as a novel mechanism by which cognitive dysfunction can arise during epileptogenesis and suggest a potential disease-modifying therapeutic approach to target it. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Neurobiology of Disease
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    • "In vivo studies demonstrate that AEOL 10150 was an effective rescue agent against CEES-induced lung injury, inflammation and oxidative stress, and also improved CEES-induced olfactory epithelial injury [25] [26]. This antioxidant is reported as an effective treatment against Cl 2 lung injuries and radiation-induced pulmonary toxicity [23] [27]. "
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    ABSTRACT: Our previous studies and other published reports with the chemical warfare agent sulfur mustard (SM) and its analog 2-chloroethyl ethyl sulfide (CEES) have indicated a role of oxidative stress in skin injuries caused by these vesicating agents. We examined the effects of the catalytic antioxidant AEOL 10150 in attenuation of CEES-induced toxicity in our established skin injury models (skin epidermal cells and SKH-1 hairless mice) to validate the role of oxidative stress in the pathophysiology of mustard vesicating agents. Treatment of mouse epidermal JB6 and human HaCaT cells with AEOL 10150 (50μM) 1h post CEES exposure resulted in significant (p<0.05) reversal of CEES-induced decreases in both cell viability and DNA synthesis. Similarly, AEOL 10150 treatment 1h after CEES exposure attenuated CEES-induced DNA damage in these cells. Similar AEOL 10150 treatments also caused significant (p<0.05) reversal of CEES-induced decreases in cell viability in normal human epidermal keratinocytes. Cytoplasmic and mitochondrial reactive oxygen species measurements showed that AEOL 10150 treatment drastically ameliorated the CEES-induced oxidative stress in both JB6 and HaCaT cells. Based on AEOL 10150 pharmacokinetic studies in SKH-1 mouse skin, mice were treated with topical formulation plus subcutaneous (injection; 5mg/kg) AEOL 10150, 1h after CEES (4mg/mouse) exposure and every 4h thereafter for 12h. This AEOL 10150 treatment regimen resulted in over 50% (p<0.05) reversal in CEES-induced skin bi-fold and epidermal thickness, myeloperoxidase activity, and DNA oxidation in mouse skin. Results from this study demonstrate potential therapeutic efficacy of AEOL 10150 against CEES-mediated cutaneous lesions supporting AEOL 10150 as a medical countermeasure against SM-induced skin injuries.
    Full-text · Article · May 2014 · Free Radical Biology and Medicine
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    • "Typically oxidative stress implies that there is an imbalance between oxidant production and antioxidant and repair defenses resulting in increased steady-state levels of oxidized cellular macromolecules [15]. Many antioxidant agents are often validated by blocking the increased steady-state levels of oxidized cellular macromolecules in animal models involving oxidative stress [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]. This popular view does not account for why adaptive responses have failed, which is probably more important mechanistically than the simple fact that steady-state levels of oxidized cellular macromolecules are increasing. "
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    ABSTRACT: Evolution has favored the utilization of dioxygen (O2) in the development of complex multi-cellular organisms. O2 is actually a toxic mutagenic gas that is highly oxidizing and combustible. It is thought that plants are largely to blame for polluting the earth's atmosphere with O2 due to the development of photosynthesis by blue-green algae over 2 billion years ago. The rise of the plants and atmospheric O2 levels placed evolutionary stress on organisms to adapt or become extinct. This implies that all the surviving creatures on our planet are mutants that have adapted to the "abnormal biology of O2." Much of the adaptation to the presence of O2 in biological systems comes from well coordinated antioxidant and repair systems that focus on converting O2 to its most reduced form, water (H2O) and the repair and replacement of damaged cellular macromolecules. Biological systems have also harnessed O2's reactive properties for energy production, xenobiotic metabolism, host defense, and as a signaling messenger and redox modulator of a number of cell signaling pathways. Many of these systems involve electron transport systems and offer many different mechanisms by which antioxidant therapeutics can alternatively produce an antioxidant effect without directly scavenging oxygen-derived reactive species. It is likely that each agent will have a different set of mechanisms that may change depending of the model of oxidative stress, organ system, or disease state. An important point is that all biological processes of aerobes have co-evolved with O2 and this creates a Pandora's Box for trying to understand the mechanism of action(s) of antioxidants being developed as therapeutic agents.
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Questions & Answers about this publication

  • Toby K Mcgovern added an answer in Oxidative Stress:
    What factors effect oxidative stress in diseases?
    I have studied a lot about oxidative stress in COPD and asthma and have heard a bit about its induction during environmental factors. For e.g. the heat of cold induces it. Actually, I don't know the molecular mechanism. Cancer cells have high oxidative stress too.
    Toby K Mcgovern
    Hello,

    Some of the factors affecting oxidative stress can be broken down into endogenous and exogenous factors. Endogenous oxidative stress can come from activated cells, like neutrophils, which produce MPO when activated, which can result in the formation of hypochlorous acid, a potent oxidant. Also, the innate production of endogenous antioxidants like GSH or NRF2 activity will affect how the body deals with oxidative stress. If one's endogenous antioxidant response system is compromised, oxidative stress levels will rise.

    Exogenous oxdiant stress can come from the inhalation of toxic gases, like chlorine for example. Other inhalational exposures to substances like ozone, ammonia compounds and even diesel exhaust can exacerbate lung injury and induce the production of ROS. Chlorine, for example, breaks down into HCL and HOCl when in contact with water through a hydrolysis reaction. I have attached some papers that might help explain some of these concepts.

    Best of luck!

    Toby
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      [Show abstract] [Hide abstract]
      ABSTRACT: New therapeutics designed as rescue treatments after toxic gas injury such as from chlorine (Cl(2)) are an emerging area of interest. We tested the effects of the metalloporphyrin catalytic antioxidant AEOL10150, a compound that scavenges peroxynitrite, inhibits lipid peroxidation, and has SOD and catalase-like activities, on Cl(2)-induced airway injury. Balb/C mice received 100ppm Cl(2) gas for 5 min. Four groups were studied: Cl(2) only, Cl(2) followed by AEOL10150 1 and 9 h after exposure, AEOL10150 only, and control. Twenty-four hours after Cl(2) gas exposure airway responsiveness to aerosolized methacholine (6.25-50mg/ml) was measured using a small-animal ventilator. Bronchoalveolar lavage (BAL) was performed to assess airway inflammation and protein. Whole lung tissue was assayed for 4-hydroxynonenal. In separate groups, lungs were collected at 72 h after Cl(2) injury to evaluate epithelial cell proliferation. Mice exposed to Cl(2) showed a significantly higher airway resistance compared to control, Cl(2)/AEOL10150, or AEOL10150-only treated animals in response to methacholine challenge. Eosinophils, neutrophils, and macrophages were elevated in BAL of Cl(2)-exposed mice. AEOL10150 attenuated the increases in neutrophils and macrophages. AEOL10150 prevented Cl(2)-induced increase in BAL fluid protein. Chlorine induced an increase in the number of proliferating airway epithelial cells, an effect AEOL10150 attenuated. 4-Hydroxynonenal levels in the lung were increased after Cl(2) and this effect was prevented with AEOL10150. AEOL10150 is an effective rescue treatment for Cl(2)-induced airway hyperresponsiveness, airway inflammation, injury-induced airway epithelial cell regeneration, and oxidative stress.
      Full-text · Article · Mar 2011 · Free Radical Biology and Medicine