N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury

Marta Celorrio, James Rhodes, Sangeetha Vadivelu, McKenzie Davies, Stuart H. Friess

Research output: Contribution to journalArticlepeer-review

Abstract

Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain's resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes.

Original languageEnglish
Article number113507
JournalExperimental Neurology
Volume335
DOIs
StatePublished - Jan 2021

Keywords

  • Hypoxemia
  • N-acetylcysteine
  • Neuroprotection
  • Pre-clinical trial
  • Secondary injury
  • Traumatic brain injury

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