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Bajorat R, Grest SL, Bergt S, Klawitter F, Vollmar B, Reuter DA, Bajorat J. Administration of Delphinidin to Improve Survival and Neurological Outcome in Mice After Cardiac Arrest and Resuscitation. Antioxidants (Basel) 2024; 13:1469. [PMID: 39765798 PMCID: PMC11672804 DOI: 10.3390/antiox13121469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Reactive oxygen species (ROS) play an important role in ischemia-reperfusion (I/R) after cardiac arrest and cardiopulmonary resuscitation (CA-CPR). Early administration of vitamin C at a high dose in experimental models resulted in less myocardial damage and had a positive effect on survival after resuscitation. Here, we postulated that the ROS scavenging activity of an anthocyanin (i.e., delphinidin) would positively influence resuscitation outcomes. We hypothesized that administration of delphinidin immediately after CA-CPR could attenuate systemic inflammation in a standardized mouse model and thereby improve survival and long-term outcomes. Outcomes up to 28 days were evaluated in a control group (saline-treated) and a delphinidin-treated cohort. Survival, neurological and cognitive parameters were assessed. Post-CPR infusion of delphinidin deteriorated survival time after a 10 min CA. Survivors amongst the controls showed significantly more anxious behavior than in the pre-CPR phases. This tendency was also observed in the animals treated with delphinidin. In our study, we did not find an improvement in survival with delphinidin after CA-CPR and observed no effect on learning behavior. Our long-term behavioral tests clearly show that CA-CPR is associated with the development of post-interventional anxiety-like symptoms. Our findings open up scopes to investigate the intrinsic factors (e.g., oxidative stress, inflammatory and systemic-microbial response, etc.) influencing the therapeutic efficacy of anthocyanins in vivo.
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Affiliation(s)
- Rika Bajorat
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
| | - Stella Line Grest
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
- Department of Psychosomatic Medicine and Psychotherapy, Rostock University Medical Center, Goethestraße 18, 18055 Rostock, Germany
| | - Stefan Bergt
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
- Department of Anesthesiology and Intensive Care Medicine, Mediclin, 17192 Waren, Germany
| | - Felix Klawitter
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
| | - Brigitte Vollmar
- Institute of Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany
| | - Daniel A. Reuter
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
| | - Jörn Bajorat
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany
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Yoladi FB, Palabiyik-Yucelik SS, Bahador Zirh E, Halici Z, Baydar T. Effects of idebenone and coenzyme Q10 on NLRP3/caspase-1/IL-1β pathway regulation on ethanol-induced hepatotoxicity in rats. Drug Chem Toxicol 2024; 47:1205-1217. [PMID: 38804209 DOI: 10.1080/01480545.2024.2351191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 04/29/2024] [Indexed: 05/29/2024]
Abstract
Chronic and excessive alcohol consumption leads to liver toxicity. There is a need to investigate effective therapeutic strategies to alleviate alcohol-induced liver injury, which remains the leading cause of liver-related morbidity and mortality worldwide. Therefore here, we looked into and evaluated how ethanol-induced hepatotoxicity was affected by coenzyme Q10 (CoQ10) and its analog, idebenone (IDE), on the NLRP3/caspase-1/IL-1 pathway. Hepatotoxicity induced in rats through the oral administration of gradually increasing dosages of ethanol (from 2 to 6 g/kg/day) over 30 days and the effect of CoQ10 (10 or 20 mg/kg) and IDE (50 or 100 mg/kg) were evaluated. Serum hepatotoxicity markers (ALT, AST, GGT, ALP, and TBIL), tissue oxidative stress markers and the mRNA expressions of IL-1β, IL-18, TGF-β, NF-κB, NLRP3, and caspase-1 were evaluated. Masson's trichrome staining was also used to visualize fibrosis in the liver tissue. The results indicated that ethanol exposure led to hepatotoxicity as well as considerable NLRP3/caspase-1/IL-1β pathway activation. Moreover, CoQ10 or IDE treatment reduced measured parameters in a dosage-dependent manner. Thus, by inhibiting the NLRP3/caspase-1/IL-1 pathway, CoQ10 and IDE can prevent the hepatotoxicity caused by ethanol, although CoQ10 is more effective than IDE. This study will provide insight into new therapeutic avenues that take advantage of the anti-inflammatory and antioxidant properties of CoQ10 and IDE in ethanol-induced liver diseases.
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Affiliation(s)
- Fatma Betül Yoladi
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
- Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Saziye Sezin Palabiyik-Yucelik
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Atatürk University, Erzurum, Turkey
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ondokuz Mayıs University, Samsun, Turkey
| | - Elham Bahador Zirh
- Department of Histology and Embryology, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey
| | - Zekai Halici
- Clinical Research, Development and Design Application and Research Center, Atatürk University, Erzurum, Turkey
- Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Terken Baydar
- Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
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Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats. BIOLOGY 2022; 11:biology11070957. [PMID: 36101338 PMCID: PMC9312251 DOI: 10.3390/biology11070957] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/11/2022] [Accepted: 06/21/2022] [Indexed: 11/17/2022]
Abstract
Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials.
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Coenzyme Q 10 Analogues: Benefits and Challenges for Therapeutics. Antioxidants (Basel) 2021; 10:antiox10020236. [PMID: 33557229 PMCID: PMC7913973 DOI: 10.3390/antiox10020236] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 01/31/2023] Open
Abstract
Coenzyme Q10 (CoQ10 or ubiquinone) is a mobile proton and electron carrier of the mitochondrial respiratory chain with antioxidant properties widely used as an antiaging health supplement and to relieve the symptoms of many pathological conditions associated with mitochondrial dysfunction. Even though the hegemony of CoQ10 in the context of antioxidant-based treatments is undeniable, the future primacy of this quinone is hindered by the promising features of its numerous analogues. Despite the unimpeachable performance of CoQ10 therapies, problems associated with their administration and intraorganismal delivery has led clinicians and scientists to search for alternative derivative molecules. Over the past few years, a wide variety of CoQ10 analogues with improved properties have been developed. These analogues conserve the antioxidant features of CoQ10 but present upgraded characteristics such as water solubility or enhanced mitochondrial accumulation. Moreover, recent studies have proven that some of these analogues might even outperform CoQ10 in the treatment of certain specific diseases. The aim of this review is to provide detailed information about these Coenzyme Q10 analogues, as well as their functionality and medical applications.
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Zhou M, Yu T, Fang X, Ge Q, Song F, Huang Z, Jiang L, Wang P. Short-term dietary restriction ameliorates brain injury after cardiac arrest by modulation of mitochondrial biogenesis and energy metabolism in rats. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:8. [PMID: 33553301 PMCID: PMC7859767 DOI: 10.21037/atm-20-3075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background Dietary restriction (DR) is a well-known intervention that increases lifespan and resistance to multiple forms of acute stress, including ischemia reperfusion injury. However, the effect of DR on neurological injury after cardiac arrest (CA) remains unknown. Methods The effect of short-term DR (one week of 70% reduced daily diet) on neurological injury was investigated in rats using an asphyxial CA model. The survival curve was obtained using Kaplan-Meier survival analysis. Serum S-100β levels were detected by enzyme linked immunosorbent assay. Cellular apoptosis and neuronal damage were assessed by terminal deoxyribonucleotide transferase dUTP nick end labeling assay and Nissl staining. The oxidative stress was evaluated by immunohistochemical staining of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Mitochondrial biogenesis was examined by electron microscopy and mitochondrial DNA copy number determination. The protein expression was detected by western blot. The reactive oxygen species (ROS) and metabolite levels were measured by corresponding test kits. Results Short-term DR significantly improved 3-day survival, neurologic deficit scores (NDS) and decreased serum S-100β levels after CA. Short-term DR also significantly attenuated cellular apoptosis, neuronal damage and oxidative stress in the brain after CA. In addition, short-term DR increased mitochondrial biogenesis as well as brain PGC-1α and SIRT1 protein expression after CA. Moreover, short-term DR increased adenosine triphosphate, β-hydroxybutyrate, acetyl-CoA levels and nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) ratios as well as decreased serum lactate levels. Conclusions Reduction of oxidative stress, upregulation of mitochondrial biogenesis and increase of ketone body metabolism may play a crucial role in preserving neuronal function after CA under short-term DR.
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Affiliation(s)
- Minggen Zhou
- Department of Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tao Yu
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Xiangshao Fang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Qiulin Ge
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Fengqing Song
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Zitong Huang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Longyuan Jiang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
| | - Peng Wang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou, China
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Border between natural product and drug: comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biol 2015; 4:289-95. [PMID: 25625583 PMCID: PMC4803797 DOI: 10.1016/j.redox.2015.01.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 01/12/2015] [Accepted: 01/12/2015] [Indexed: 12/23/2022] Open
Abstract
Coenzyme Q10 is a ubiquitous component of cellular membranes and belongs to the class of benzoquinones that mainly differ with regards to the length and composition of their hydrophobic tail. The characteristic quinone group can accept electrons from various biological sources and is converted by a one electron transfer to the unstable semiquinone or by a two electron transfer to the more stable hydroquinone. This feature makes CoQ10 the bona fide cellular electron transfer molecule within the mitochondrial respiratory chain and also makes it a potent cellular antioxidant. These activities serve as justification for its popular use as food supplement. Another quinone with similarities to the naturally occurring CoQ10 is idebenone, which shares its quinone moiety with CoQ10, but at the same time differs from CoQ10 by the presence of a much shorter, less lipophilic tail. However, despite its similarity to CoQ10, idebenone cannot be isolated from any natural sources but instead was synthesized and selected as a pharmacologically active compound in the 1980s by Takeda Pharmaceuticals purely based on its pharmacological properties. Several recent clinical trials demonstrated some therapeutic efficacy of idebenone in different indications and as a consequence, many practitioners question if the freely available CoQ10 could not be used instead. Here, we describe the molecular and pharmacological features of both molecules that arise from their structural differences to answer the question if idebenone is merely a CoQ10 analogue as frequently perpetuated in the literature or a pharmaceutical drug with entirely different features.
The benzoquinones CoQ10 and idebenone have vastly different solubility. Both molecules need to get activated by cellular reductases. Due to their solubility both molecules are in different cellular compartments. Therefore, both quinones are activated by different enzymes. Thus, their solubility strongly determines their biological activities.
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Fiebiger SM, Bros H, Grobosch T, Janssen A, Chanvillard C, Paul F, Dörr J, Millward JM, Infante-Duarte C. The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse. J Neuroimmunol 2013; 262:66-71. [PMID: 23871488 DOI: 10.1016/j.jneuroim.2013.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 06/08/2013] [Accepted: 07/02/2013] [Indexed: 10/26/2022]
Abstract
Oxidative stress and mitochondrial dysfunction appear to contribute to neurodegenerative processes during multiple sclerosis (MS). Thus, antioxidants may represent a therapeutic option for MS. The antioxidant idebenone was proven to be beneficial in Friedreich's ataxia and Leber's hereditary optic neuropathy, two disorders caused by mitochondrial alterations. Here we showed that idebenone protected neuronal HT22 cells from glutamate-induced death in vitro. However, in experimental autoimmune encephalomyelitis, idebenone failed to affect disease incidence or onset when applied preventively, or to reduce disease severity when applied therapeutically. Histopathological examination of CNS from idebenone treated mice showed no improvement in inflammation, demyelination, or axonal damage. Thus, we hypothesize that idebenone treatment will likely not benefit patients with MS.
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Affiliation(s)
- Sebastian M Fiebiger
- Institute for Medical Immunology, Charité-Universitätmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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Dokken BB, Piermarini CV, Teachey MK, Gura MT, Dameff CJ, Heller BD, Krate J, Ashgar AM, Querin L, Mitchell JL, Hilwig RW, Kern KB. Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects. Am J Physiol Heart Circ Physiol 2012; 304:H538-46. [PMID: 23241323 DOI: 10.1152/ajpheart.00282.2012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has protective effects in the heart. We hypothesized that GLP-1 would mitigate coronary microvascular and left ventricular (LV) dysfunction if administered after cardiac arrest and resuscitation (CAR). Eighteen swine were subjected to ventricular fibrillation followed by resuscitation. Swine surviving to return of spontaneous circulation (ROSC) were randomized to receive an intravenous infusion of either human rGLP-1 (10 pmol·kg(-1)·min(-1); n = 8) or 0.9% saline (n = 8) for 4 h, beginning 1 min after ROSC. CAR caused a decline in coronary flow reserve (CFR) in control animals (pre-arrest, 1.86 ± 0.20; 1 h post-ROSC, 1.3 ± 0.05; 4 h post-ROSC, 1.25 ± 0.06; P < 0.05). GLP-1 preserved CFR for up to 4 h after ROSC (pre-arrest, 1.31 ± 0.17; 1 h post-ROSC, 1.5 ± 0.01; 4 h post-ROSC, 1.55 ± 0.22). Although there was a trend toward improvement in LV relaxation in the GLP-1-treated animals, overall LV function was not consistently different between groups. 8-iso-PGF(2α), a measure of reactive oxygen species load, was decreased in post-ROSC GLP-1-treated animals [placebo, control (NS): 38.1 ± 1.54 pg/ml; GLP-1: 26.59 ± 1.56 pg/ml; P < 0.05]. Infusion of GLP-1 after CAR preserved coronary microvascular and LV diastolic function. These effects may be mediated through a reduction in oxidative stress.
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Affiliation(s)
- Betsy B Dokken
- Department of Medicine, University of Arizona, Tucson, AZ, USA.
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Ali SA, Aly HF, Faddah LM, Zaidi ZF. Dietary supplementation of some antioxidants against hypoxia. World J Gastroenterol 2012; 18:6379-6386. [PMID: 23197883 PMCID: PMC3508632 DOI: 10.3748/wjg.v18.i44.6379] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 07/19/2012] [Accepted: 07/28/2012] [Indexed: 02/06/2023] Open
Abstract
The present study aims to clarify the protective effect of supplementation with some antioxidants, such as idebenone (200 mg/kg, ip), melatonin (10 mg/kg, ip) and arginine (200 mg/kg, ip) and their combination, on liver function (T. protein, albumin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase), energetic parameters (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, inorganic phosphate, total adenylate, adenylate energy charge and potential phosphate). The effect on glycolytic and glycogenolytic enzymes (glucose, glycogen, glycogen phosphorylase, pyruvate kinase and phosphofructokinase against hypoxia) was also studied. The drugs were administered 24 and 1 h prior sodium nitrite intoxication. All biochemical parameters were estimated 1 h after sodium nitrite injection. Injection of sodium nitrite (75 mg/kg, sc) produced a significant disturbance in all biochemical parameters of liver function, energetic parameters and glycolytic and glycogenolytic enzymes. Hepatic damage was confirmed by histopathological examination of the liver as compared to controls. The marked changes in hepatic cells induced by sodium nitrite were completely abolished by pretreatment with the drug combination, suggesting potential protection against sodium nitrite-induced hypoxia. It could be concluded that a combination of both idebenone and melatonin or idebenone and arginine provides potential protection against sodium nitrite-induced hypoxia by improving biochemical parameters and preserving liver histology.
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Abstract
An increase in oxidative stress and overproduction of oxidizing reactive species plays an important role in the pathophysiology of several conditions encountered in the neurocritical care setting including: ischemic and hemorrhagic strokes, traumatic brain injury, acute respiratory distress syndrome, sepsis, and organ failure. The presence of oxidative stress in these conditions is supported by a large body of pre-clinical and clinical studies, and provides a rationale to support a potential therapeutic role for antioxidants. The purpose of this article is to briefly review the basic mechanisms and molecular biology of oxidative stress, summarize its role in critically ill neurological patients, and review available data regarding the potential role of antioxidant strategies in neurocritical care and future directions.
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Affiliation(s)
- Khalid A. Hanafy
- Department of Neurology, Divisions of Neurocritical Care, Beth Israel Deaconess Medical Center, Boston, MA 02215 USA
| | - Magdy H. Selim
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue – Palmer 127, Boston, MA 02215 USA
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Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PLoS One 2011; 6:e28855. [PMID: 22205977 PMCID: PMC3242749 DOI: 10.1371/journal.pone.0028855] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 11/16/2011] [Indexed: 01/17/2023] Open
Abstract
Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD.
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Abdel Baky NA, Zaidi ZF, Fatani AJ, Sayed-Ahmed MM, Yaqub H. Nitric oxide pros and cons: The role of L-arginine, a nitric oxide precursor, and idebenone, a coenzyme-Q analogue in ameliorating cerebral hypoxia in rat. Brain Res Bull 2010; 83:49-56. [PMID: 20637840 DOI: 10.1016/j.brainresbull.2010.07.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2010] [Revised: 07/06/2010] [Accepted: 07/07/2010] [Indexed: 10/19/2022]
Abstract
Evidence exists that nitric oxide (NO) may mediate both protective and pathological responses during brain hypoxia (HP). Reactive oxygen species have also been implicated in the pathophysiological response of the brain tissues to HP. Therefore, this study investigated whether a NO precursor, l-arginine (l-arg), a free radical scavenger, idebenone (ID), and their combination would reduce neurological injury resulting from hemic hypoxia (HP) in rats. Adult male Wistar albino rats were injected with sodium nitrite (60 mg/kg, s.c.) to establish hemic hypoxia. ID (100 mg kg(-1), i.p.) and/or l-arg (100 mg kg(-1), i.p.) were administrated 24 and 1h prior to sodium nitrite intoxication, respectively. Hypoxia significantly decreased hemoglobin concentration, while significantly increased serum lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total nitrate/nitrite, sialic, and uric acids concentrations. Moreover, brain lipid peroxides were significantly enhanced, while reduced glutathione, l-ascorbic acids, adenosine triphosphate (ATP) contents, and the activities of catalase and superoxide dismutase, were significantly reduced in the brain tissue. Pretreatment with either ID or l-arg altered the majority of the above-mentioned biochemical changes in hypoxic rats. Additionally, the combination of these two agents significantly reduced injury marker enzyme activities as well as serum sialic, and uric acids level (P>0.05 vs. control). Moreover, this combination exerted a synergistic antioxidant effect by blocking the induction of lipid peroxidation, preserving brain energy (ATP) content, and greatly reducing the hypoxic alterations in brain enzymatic and non-enzymatic antioxidants. Histopathological examination of the brain tissue supported these biochemical findings. This study showed that ID and l-arg were capable of reducing neurological injury following HP in rat, and support the idea of the usefulness of l-arg and ID as prophylaxis from hypoxic brain injury.
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Affiliation(s)
- Nayira A Abdel Baky
- Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
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Morris MC, Nadkarni VM. Pediatric cardiopulmonary-cerebral resuscitation: an overview and future directions. Crit Care Clin 2003; 19:337-64. [PMID: 12848310 DOI: 10.1016/s0749-0704(03)00003-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The evolving understanding of pathophysiologic events during and after pediatric cardiac arrest has not yet resulted in significantly improved outcome. Exciting breakthroughs in basic and applied science laboratories are, however, on the immediate horizon for study in specific subpopulations of cardiac arrest victims. Strategically focusing therapies to specific phases of cardiac arrest and resuscitation and evolving pathophysiologic events offers great promise that critical care interventions will lead the way to more successful cardiopulmonary and cerebral resuscitation in children.
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Affiliation(s)
- Marilyn C Morris
- Department of Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA
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Sulkowski G, Waśkiewicz J, Walski M, Januszewski S, Rafałowska U. Synaptosomal susceptibility on global ischaemia caused by cardiac arrest correlated with early and late times after recirculation in rats. Resuscitation 2002; 52:203-13. [PMID: 11841889 DOI: 10.1016/s0300-9572(01)00451-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The aim of the study was to assess the sensitivity of brain synaptosomes and their mitochondria to the effects of global cerebral ischaemia caused by temporary cardiac arrest and the early and late consequences. The effects of 10 min of global ischaemia were measured immediately and after 1 h, 24 h and 7 days post-resuscitation. Ischaemia caused a reduction in oxygen consumption by synaptosomes of about 20%, a drop in ATP/ADP ratio of about 40%, a decrease in CrP/Cr ratio at about 45% and a reduction of synaptic vesicles and disturbances in the mitochondrial structure in isolated synaptosomes and in nerve endings of brain specimens. Morphometric analysis showed that ischaemic conditions caused a decrease in synaptic vesicles by about 61% and an increase of mitochondrial damage to 58 and 50% after 1 and 24 h postreperfusion time, respectively. Seven days postresuscitation, all the observed changes returned to normal but small numbers (about 2%) of neurones which were destroyed neurons appeared at that time. It is concluded that global ischaemia with early resuscitation after cardiac arrest may lead to damage of synaptosomes and synaptic mitochondria. This, in turn, modifies substrate oxidation, synthesis of energy variables and affects neurotransmitter function. The observed disturbances return to normal later after resuscitation but the ischaemic events and reoxygenation caused selective morphological injury of certain neurones and this may form the basis for irreversible brain damage.
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Affiliation(s)
- Grzegorz Sulkowski
- Laboratory of Pathobiochemistry of the Central Nervous System, Department of Neurochemistry, Medical Research Centre Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw, Poland
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Palumbo M, Russo A, Cardile V, Renis M, Paolino D, Puglisi G, Fresta M. Improved antioxidant effect of idebenone-loaded polyethyl-2-cyanoacrylate nanocapsules tested on human fibroblasts. Pharm Res 2002; 19:71-78. [PMID: 11837703 DOI: 10.1023/a:1013659516878] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE The protective antioxidant role of idebenone both as free drug and drug-loaded Tween 80-coated polyethyl-2-cyanoacrylate (PECA) nanocapsules is reported. The relationship between oxidative damage and apoptotic or nonapoptotic cell death is evaluated in vitro. METHODS Idebenone-loaded nanocapsules were prepared with the interfacial polymerization method in the presence of Tween 80. Human nonimmortalized fibroblasts. under different stress conditions, either 0.5 mM diethylmaleate (DEM) for 60 min or 0.1 mM H2O2 for 30 min, were used as the experimental in vitro model. The production of reactive oxygen species, the cell viability, and the nuclear DNA damage were evaluated. The presence of apoptotic damage was evaluated both by the determination of caspase-3-like protein activity and by Promega's fluorescent apoptotic detection system. RESULTS DEM and H2O2 affected the cultured cells in different ways. DEM induced a moderate cellular insult, which was efficaciously antagonized by idebenone-loaded PECA nanocapsules. H2O2 elicited severe damage to nuclear DNA, which was reduced by idebenoneloaded PECA nanocapsules. The free drug was less effective than idebenone-loaded nanocapsules. CONCLUSIONS The findings reported here demonstrate that an improved antioxidant effect was obtained with a low idebenone concentration (0.5 microM) when the drug was entrapped within Tween 80-coated PECA nanocapsules.
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Joanny P, Steinberg J, Robach P, Richalet JP, Gortan C, Gardette B, Jammes Y. Operation Everest III (Comex'97): the effect of simulated sever hypobaric hypoxia on lipid peroxidation and antioxidant defence systems in human blood at rest and after maximal exercise. Resuscitation 2001; 49:307-14. [PMID: 11723998 DOI: 10.1016/s0300-9572(00)00373-7] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Eight subjects were placed in a decompression chamber for 31 days at pressures from sea level (SL) to 8848 m altitude equivalent. Whole blood lipid peroxidation (LP) was increased at 6000 m by a mean of 23% (P<0.05), at 8000 m by 79% (P<0.01) and at 8848 m by 94% (P<0.01). (All figures are means.) Two days after return to sea level (RSL), it remained high, by 81% (P<0.01), while corresponding erythrocyte GSH/GSSG ratios decreased by 31, 46, 49, 48%, respectively (each P<0.01). Erythrocyte SOD and plasma ascorbate did not change significantly. At sea level, maximal exercise induced a 49% increase in LP (P<0.01), and a 27% decrease in erythrocyte GSH/GSSG ratio relative to resting values (P<0.05). At 6000 m, the LP was enhanced further from 23 (P<0.05) to 66% (P<0.01), and after RSL from 81 (P<0.01) to 232% (P<0.01), while pre-exercise GSH/GSSG ratios did not change significantly. Exercise did not change plasma ascorbate relative to sea level or to 6000 m, but decreased after RSL by 32% (P<0.01). These findings suggest that oxidative stress is induced by prolonged hypobaric hypoxia, and is maintained by rapid return to sea level, similar to the post-hypoxic re-oxygenation process. It is increased by physical exercise.
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Affiliation(s)
- P Joanny
- INSERM U 501, Interactions Fonctionnelles en Neuroendocrinologie, Institut Jean Roche, Faculté de Médecine de Marseilles, France
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Stvolinsky S, Kukley M, Dobrota D, Mezesova V, Boldyrev A. Carnosine protects rats under global ischemia. Brain Res Bull 2000; 53:445-8. [PMID: 11137002 DOI: 10.1016/s0361-9230(00)00366-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Rat brain subjected to 45-min global ischemia is characterized by decreased activity of K-p-nitrophenyl phosphatase and monoamine oxidase B and a disordering of the membrane bilayer by reactive oxygen species attack, the latter being monitored by the fluorescence of the membrane fluorescent probe, 1-anilino, 8-naphtalene sulphonate (ANS). Ischemic injury resulted in 67% mortality of the animals. In the group of animals pre-treated with the neuropeptide carnosine the mortality was only 30%. At the same time, carnosine protected both the activity of the above-mentioned enzymes and the brain membrane disordering, which was also tested by ANS fluorescence. The conclusion was made that carnosine protects the brain against oxidative injury and thereby increases the survival of the animals.
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Affiliation(s)
- S Stvolinsky
- Laboratory of Neurochemistry, Institute of Neurology, Russian Academy of Medical Sciences, Moscow, Russia
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Rafałowska U, Sulkowski G, Waśekiewicz J, Januszewski S, Kapuościñski A. Alteration of dopamine transport and dopamine D(2) receptor binding in the brain induced by early and late consequences of global ischaemia caused by cardiac arrest in the rat. Resuscitation 2000; 47:195-201. [PMID: 11008159 DOI: 10.1016/s0300-9572(00)00224-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
This study was designed to determine the effects of global cerebral ischaemia caused by temporary cardiac arrest and the early and late consequences of this ischaemia on dopamine transport and dopamine D(2) receptor binding in rat brain. The effects of 10 min of global ischaemia were measured immediately and after 1 h and 7 days post-resuscitation. A decrease of dopamine uptake in the rats by synaptosomes was noted immediately following global ischaemia and 1 h after resuscitation. However, at 7 days post-resuscitation, the dopamine uptake returned to control values. Reversibility of the changes in the synaptosomal dopamine uptake is undoubtedly a favourable sign. Global ischaemia and reperfusion after 1 h or 7 days did not show altered rates of dopamine release but did affect the dopamine D(2) receptor. An observed increase of receptor affinity may be an adaptive response to the reduction in binding capacity. The reduction of visible D(2) receptor binding sites in the early post-resuscitation phase, which was extended to the period of 7 days after resuscitation without recovery, is probably associated with neuronal necrotic damage.
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Affiliation(s)
- U Rafałowska
- Laboratory of Pathobiochemistry of the Central Nervous System, Department of Neurochemistry, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106, Warsaw, Poland
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Gallant S, Kukley M, Stvolinsky S, Bulygina E, Boldyrev A. Effect of carnosine on rats under experimental brain ischemia. TOHOKU J EXP MED 2000; 191:85-99. [PMID: 10946918 DOI: 10.1620/tjem.191.85] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The effect of dietary carnosine on the behavioral and biochemical characteristics of rats under experimental ischemia was studied. Carnosine was shown to improve the animals orientation and learning in "Open Field" and "T-Maze" tests, and this effect was accompanied with an increase in glutamate binding to N-methyl-D-aspartate (NMDA) receptors in brain synaptosomes. Long-term brain ischemia induced by both sides' occlusion of common carotid arteries resulted in 55% mortality of experimental rats, and those who survived were characterized by partial suppression of orientation in T-maze. In the group of rats treated with carnosine, mortality after ischemic attack was decreased (from 55% to 17%) and most of the learning parameters were kept at the pre-ischemic level. Monoamine oxidase B (MAO B) activity in brain of the carnosine treated rats was not changed by ischemia significantly (compared to that of ischemic untreated rats) but NMDA binding to brain synaptosomal membranes being increased by ischemic attack was significantly suppressed and reached the level characteristic of normal brain. The suggestion was made that carnosine possesses a dual effect on NMDA receptors resulting in increase in their amount after long-term treatment but decrease the capacity to bind NMDA after ischemic attack.
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Affiliation(s)
- S Gallant
- Zoetic Neurosciences Ltd., England, UK
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