Dataset Information

The influence of catabolic reactions on polyamine excretion.

ABSTRACT: Complete inhibition of polyamine catabolism is possible by combined administration of two compounds. Aminoguanidine (25 mg/kg body wt., intraperitoneally) inhibits all reactions that are catalysed by copper-containing amine oxidases (CuAO). The products of the CuAO-catalysed reactions cannot be reconverted into polyamines (terminal catabolism) and therefore usually escape observation. N1-Methyl-N2-(buta-2,3-dienyl)butane-1,4-diamine (MDL 72521) is a new inhibitor of polyamine oxidase. It inhibits completely the degradation of N1-acetylspermidine and N1-acetylspermine. The enhanced excretion of N1-acetylspermidine in urine after administration of 20 mg of MDL 72521/day per kg body wt. is a measure of the rate of spermidine degradation in vivo to putrescine, and thus of the quantitative significance of the interconversion pathway. From the enhancement of total polyamine excretion by aminoguanidine-treated rats, one can calculate that only about 40% of the polyamines that are destined for elimination are usually observed in the urine, the other 60% being catabolized along the CuAO-catalysed pathways. The normally observed urinary polyamine pattern gives, therefore, an unsatisfactory picture of the actual polyamine elimination. Although aminoguanidine alone is sufficient to block terminal polyamine catabolism, rats that were treated with a combination of aminoguanidine and MDL 72521 excrete more polyamines than those that received aminoguanidine alone. The reason is that a certain proportion of putrescine, which is formed by degradation of spermidine, is normally reutilized for polyamine biosynthesis. In MDL 72521-treated animals this proportion appears in the urine in the form of N1-acetylspermidine. Thus it is possible to determine polyamine interconversion and re-utilization in vivo and to establish a polyamine balance in intact rats by using specific inhibitors of the CuAO and of polyamine oxidase.

SUBMITTER: Seiler N

PROVIDER: S-EPMC1144572 | biostudies-other | 1985 Jan

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:BackgroundPolyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity.MethodsMice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox-/-) and Sat1-KO (Sat1-/-) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses.ResultsSmox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/Sat1-dKO mice.ConclusionsThese results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.

Dataset Information

The influence of catabolic reactions on polyamine excretion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets