Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.
Sarah PielJoanna I JanowskaJ Laurenson WardMeagan J McManusJoshua S JoseJonathan StarrMalkah SheldonCarly L ClaymanEskil ElmérMagnus J HanssonDavid H JangMichael KarlssonJohannes K EhingerTodd J KilbaughPublished in: Scientific reports (2022)
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.
Keyphrases
- brain injury
- liver failure
- subarachnoid hemorrhage
- respiratory failure
- drug induced
- aortic dissection
- healthcare
- oxidative stress
- public health
- risk assessment
- hepatitis b virus
- young adults
- stem cells
- physical activity
- bone marrow
- cancer therapy
- quality improvement
- intensive care unit
- mouse model
- depressive symptoms
- cardiovascular events
- cell therapy
- drug delivery
- health insurance
- simultaneous determination
- replacement therapy
- respiratory tract