Elevated N¹‐Acetylspermidine Levels in Gerbil and Rat Brains After CNS Injury

Abstract

Abstract:The polyamine system is very sensitive to different pathological states of the brain and is perturbed after CNS injury. The main modifications are significant increases in ornithine decarboxylase activity and an increase in tissue putrescine levels. Previously we have shown that the specific polyamine oxidase (PAO) inhibitor N 1 ,N 4 -bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527) reduced the tissue putrescine levels, edema, and infarct volume after transient focal cerebral ischemia in spontaneously hypertensive rats and traumatic brain injury of Sprague-Dawley rats. In the present study, N 1 -acetylspermidine accumulation was greater in injured brain regions compared with sham or contralateral regions following inhibition of PAO by MDL 72527. This indicates spermidine/spermine-N 1 -acetyltransferase (SSAT) activation after CNS injury. The observed increase in N 1 -acetylspermidine levels at 1 day after CNS trauma paralleled the decrease in putrescine levels after treatment with MDL 72527. This suggests that the increased putrescine formation at 1 day after CNS injury is mediated by the SSAT/PAO pathway, consistent with increased SSAT mRNA after transient ischemia. Key Words: Cerebral ischemia-Spermidine/spermine-N 1 -acetyltransferase -Polyamine oxidase -MDL 72527-Putrescine -Traumatic brain injury-Polyamine interconversion pathway-Polyamines-Ornithine decarboxylase. J. Neurochem. 74, 1106Neurochem. 74, -1111Neurochem. 74, (2000.Putrescine, spermidine, and spermine are endogenous polyamines essential for cellular growth, proliferation, regeneration, and differentiation (Pegg and McCann, 1982;Morgan, 1987;Marton and Pegg, 1995). The metabolism and catabolism of polyamines are highly regulated by the concerted action of six enzymes (Paschen, 1992a,b;Marton and Pegg, 1995). The metabolism of polyamines is regulated by ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase, together with spermidine/spermine synthases, of which ODC is the rate-limiting step for the conversion of ornithine to putrescine. Spermidine/spermine-N 1 -acetyltransferase (SSAT) and polyamine oxidase (PAO) regulate polyamine catabolism and the interconversion of spermine/spermidine back to putrescine (Casero and Pegg, 1993;Woster, 1995). In normal brain tissue it has been estimated that ODC accounts for 30% of putrescine, whereas the remaining 70% is formed through the SSAT/ PAO pathway (Seiler and Bolkenius, 1985;Seiler, 1995).Alterations in polyamine metabolism have been implicated in neuronal degeneration after CNS injury (Paschen, 1992a,b;Schmitz et al

Serum Metabolomics of Slow vs. Rapid Motor Progression Parkinson’s Disease: a Pilot Study

“…Another metabolomic study [24] reported an increased level of a “biogenic amine” in the urine of PD patients; however, the identity of this amine was not described. As mentioned previously, N8-acetylspermidine is an excretion product; increases in PA excretion are associated with injury, including traumatic brain injury, as well as neuroinflammation and neuronal cell death [31,33,34]. Additionally, N8-acetylspermidine was shown to increase dopamine production in PC12 cells [35].…”

Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal

“…Brain 3-aminopropanal levels continue to increase for at least 25 h after the onset of ischemia, a time frame that corresponds to the development of spreading brain cell death. Structurally distinct inhibitors of PAO attenuate the activity of brain PAO, prevent the production of 3-aminopropanal, and significantly protect against the development of ischemic brain damage in rat models of focal cerebral ischemia and head trauma (1,(3)(4)(5).…”

Duplication and Diversification of the Spermidine/Spermine N1-acetyltransferase 1 Genes in Zebrafish

“…Accumulating evidence has indicated that mammalian Ssat1 is also involved various physiological and pathological events, including liver regeneration [6], ischemia-reperfusion injury [7], [8], [9], pancreatitis [10], [11], lipid metabolism [12], [13], carcinogenesis [14], cell migration [15], and hypoxia signaling [16], through its ability to modulate polyamine content or by directly interacting with other protein effecters, such as hypoxia inducible factor 1-α (Hif-1α) and integrin α9. Moreover, the regulation of Ssat1 is as versatile as its functions, occurring at multiple levels including transcription [17], [18], mRNA processing [19], [20], [21], translation [22], and protein stabilization [23], [24], [25].…”