title: Polyamine catabolism is enhanced after traumatic brain injury.
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-N(1)-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 (6-24 h) 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 6 h and decreased slightly at 24 h, but were normal again by 72 h post-injury. Spermidine levels also decreased slightly (6-24 h), then increased by approximately 50% at 72 h post-injury. By contrast, normally low putrescine levels increased up to sixfold (6-72 h) after TBI. Moreover, N-acetylspermidine (but not N-acetylspermine) was detectable (24-72 h) 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 72 h 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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Zahedi
authors.forename: Francis
authors.initials: F
authors.lastname: Huttinger
authors.forename: Ryan
authors.initials: R
authors.lastname: Morrison
authors.forename: Tracy
authors.initials: T
authors.lastname: Murray-Stewart
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Strauss
mesh_terms: D000123:Acetyltransferases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008660:Metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013095:Spermidine / Q000032:analysis / Q000378:metabolism; D013096:Spermine / Q000032:analysis / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D015317:Biogenic Polyamines; D015415:Biomarkers; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012333:RNA, Messenger; D013095:Spermidine; D013096:Spermine; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase