Polyamine catabolism is enhanced after traumatic brain injury

Kamyar Zahedi, Francis Huttinger, Ryan Morrison, Tracy Murray-Stewart, Robert A. Casero, Kenneth I. Strauss

Research output: Contribution to journalArticlepeer-review

Abstract

Polyamines spermine and spermidine are highly regulated, ubiquitous aliphatic cations that maintain DNA structure and function as immunomodulators and as antioxidants. Polyamine homeostasis is disrupted after brain injuries, with concomitant generation of toxic metabolites that may contribute to secondary injuries. To test the hypothesis of increased brain polyamine catabolism after traumatic brain injury (TBI), we determined changes in catabolic enzymes and polyamine levels in the rat brain after lateral controlled cortical impact TBI. Spermine oxidase (SMO) catalyzes the degradation of spermine to spermidine, generating H2O2 and aminoaldehydes. Spermidine/spermine-N1-acetyltransferase (SSAT) catalyzes acetylation of these polyamines, and both are further oxidized in a reaction that generates putrescine, H2O2, and aminoaldehydes. In a rat cortical impact model of TBI, SSAT mRNA increased subacutely (6-24h) after TBI in ipsilateral cortex and hippocampus. SMO mRNA levels were elevated late, from 3 to 7 days post-injury. Polyamine catabolism increased as well. Spermine levels were normal at 6h and decreased slightly at 24h, but were normal again by 72h post-injury. Spermidine levels also decreased slightly (6-24h), then increased by ∼50% at 72h post-injury. By contrast, normally low putrescine levels increased up to sixfold (6-72h) after TBI. Moreover, N-acetylspermidine (but not N-acetylspermine) was detectable (24-72h) near the site of injury, consistent with increased SSAT activity. None of these changes were seen in the contralateral hemisphere. Immunohistochemical confirmation indicated that SSAT and SMO were expressed throughout the brain. SSAT-immunoreactivity (SSAT-ir) increased in both neuronal and nonneuronal (likely glial) populations ipsilateral to injury. Interestingly, bilateral increases in cortical SSAT-ir neurons occurred at 72h post-injury, whereas hippocampal changes occurred only ipsilaterally. Prolonged increases in brain polyamine catabolism are the likely cause of loss of homeostasis in this pathway. The potential for simple therapeutic interventions (e.g., polyamine supplementation or inhibition of polyamine oxidation) is an exciting implication of these studies.

Original languageEnglish (US)
Pages (from-to)515-525
Number of pages11
JournalJournal of neurotrauma
Volume27
Issue number3
DOIs
StatePublished - Mar 1 2010

Keywords

  • Brain injuries
  • Colocalization immunofluorescence
  • Gene expression
  • Polyamine back-conversion
  • Polyamine quantification
  • Polyamine therapeutic potential
  • Spermidine=spermine-N1-acetyltransferase (SSAT)
  • Spermine oxidase (SMO)
  • Time course

ASJC Scopus subject areas

  • Clinical Neurology

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