Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning

Jang, David H.; Piel, Sarah; Greenwood, John C.; Kelly, Matthew; Mazandi, Vanessa; Ranganathan, Abhay; Lin, Yuxi; Starr, Jonathan; Hallowell, Thomas; Shofer, Frances S.; Lafontant, Alec; Andersen, Kristen; Ehinger, Johannes K.; Kilbaugh, Todd J.

doi:10.1080/15563650.2020.1870691

Cited by 12 publications

(13 citation statements)

References 34 publications

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“…On the other hand, CO induces apoptosis through a mechanism dependent on reactive oxygen species (ROS). Apoptosis can be one of the most common mechanisms of cardiac cell death (25).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic study of hyperbaric oxygen on Heme Oxygenase-1 (HO-1) in patients with acute carbon monoxide poisoning and myocardial injury

Wang¹,

Kong²

2022

Cell Mol Biol (Noisy-le-grand)

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“…On the other hand, CO induces apoptosis through a mechanism dependent on reactive oxygen species (ROS). Apoptosis can be one of the most common mechanisms of cardiac cell death (25).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic study of hyperbaric oxygen on Heme Oxygenase-1 (HO-1) in patients with acute carbon monoxide poisoning and myocardial injury

Wang¹,

Kong²

2022

Cell Mol Biol (Noisy-le-grand)

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“…All these characteristics favor the use of the swine for cardiovascular assessment and pharmacological studies in cardiac arrest. Our lab has established expertise in swine models of CO poisoning and cardiac arrest with the relevant physiologic and biomolecular measures that will ensure successful execution of this study from a logistical and safety perspective [ 28 , 29 , 36 , 40 , 41 ].…”

Section: Methodsmentioning

confidence: 99%

“…Lactate and pyruvate values will be used to calculate a lactate-to-pyruvate ratio (LPR) to assess for redox balance. We have extensive experience using this cMD in various animal models of critical illness related to both cardiac arrest and CO poisoning [ 28 , 29 , 40 , 46 , 47 ].…”

Section: Methodsmentioning

confidence: 99%

Carbon monoxide as a cellular protective agent in a swine model of cardiac arrest protocol

Greenwood,

Morgan,

Abella

et al. 2024

PLoS ONE

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Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50–80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.

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“…Mitochondrial function was assessed ex vivo in homogenates of the right frontal cortex. Brain homogenates (1 mg/mL) were prepared fresh as previously described and a respirometric Substrate–Uncoupler–Inhibitor Titration (SUIT) protocol was applied for in-depth characterization of the OXPHOS system and electron transport systems (ETS) 30 . Chemical reagents and concentrations used in the SUIT protocol are provided in Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

“…A commercially available kit (Acetylcholinesterase Assay Kit, Fluorometric Red, ab138873, Abcam) was used to measure AChE activity in brain and total ChE activity in serum according to the manufacturer’s instructions. Remaining brain homogenates of the sample preparation for high-resolution respirometry were further diluted to a final concentration of 1 mg/mL in the same respiratory buffer (Mir05 30 ), briefly sonicated on ice, and centrifuged for 1 min at 13,400 g at 4 °C. The supernatant was collected, and cholinesterase activity was measured in the presence of the butyrylcholinesterase inhibitor tetraisopropyl pyrophosphoramide (500 µM) to exclusively evaluate the inhibition of AChE 27 .…”

Section: Methodsmentioning

confidence: 99%

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning

Piel

Janowska

Ward

et al. 2022

Sci Rep

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Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.

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Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning

Cited by 12 publications

References 34 publications

Therapeutic study of hyperbaric oxygen on Heme Oxygenase-1 (HO-1) in patients with acute carbon monoxide poisoning and myocardial injury

Therapeutic study of hyperbaric oxygen on Heme Oxygenase-1 (HO-1) in patients with acute carbon monoxide poisoning and myocardial injury

Carbon monoxide as a cellular protective agent in a swine model of cardiac arrest protocol

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning

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