Polyamine metabolism in different pathological states of the brain

Abstract

Biosynthesis of the polyamines spermidine and spermine and their precursor putrescine is controlled by the activity of the two key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). In the adult brain, polyamine synthesis is activated by a variety of physiological and pathological stimuli, resulting most prominently in an increase in ODC activity and putrescine levels. The sharp rise in putrescine levels observed following severe cellular stress is most probably the result of an increase in ODC activity and decrease in SAMDC activity or an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Spermidine and spermine levels are usually less affected by stress and are reduced in severely injured areas. Changes of polyamine synthesis and metabolism are most pronounced in those pathological conditions that induce cell injury, such as severe metabolic stress, exposure to neurotoxins or seizure. Putrescine levels correlate closely with the density of cell necrosis. Because of the close relationship between the extent of post-stress changes in polyamine metabolism and density of cellular injury, it has been suggested that polyamines play a role in the manifestation of structural defects. Four different mechanisms of polyamine-dependent cell injury are plausible: (1) an overactivation of calcium fluxes and neurotransmitter release in areas with an overshoot in putrescine formation; (2) disturbances of the calcium homeostasis resulting from an impairment of the calcium buffering capacity of mitochondria in regions in which spermine levels are reduced; (3) an overactivation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during ischemia or after ischemia and prolonged recirculation in the tissue surrounding severely damaged areas; (4) an overproduction of hydrogen peroxide resulting from an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Insofar as a sharp activation of polyamine synthesis is a common response to a variety of physiological and pathological stimuli, studying stress-induced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.

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

“…*p Ͻ 0.05, **p Ͻ 0.01 compared with sham (n ϭ 6); # p Ͻ 0.01, MDL 72527-treated ischemic (n ϭ 5) compared with untreated ischemic with 1-day R and not significant compared with sham; ## p Ͻ 0.01, MDL 72527-treated ischemic (n ϭ 5) compared with untreated ischemic with 1-day R and p Ͻ 0.05 compared with sham. putrescine (Dempsey et al, 1991;Paschen, 1992a;Kindy et al, 1994;Rao et al, 1995Rao et al, , 1998Henley et al, 1996;Başkaya et al, 1996a,b). These changes correlate with the degree of injury and with neuronal death (Kindy et al, 1994;Henley et al, 1996;Ivanova et al, 1998).…”

“…Several mechanisms of polyamine-dependent neuronal injury have been proposed: (a) overactivation of calcium fluxes and neurotransmitter release in areas with an overproduction of putrescine (Koenig et al, 1983); (b) overstimulation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during or after CNS trauma; or (c) production of hydrogen peroxide and 3-acetamidopropanal through activation of the interconversion of spermine and spermidine into putrescine via SSAT/PAO (Morgan, 1987(Morgan, , 1998Paschen, 1992a;Seiler, 1995). SSAT is the rate-limiting step in the catabolism of polyamines (Casero and Pegg, 1993;Suppola et al, 1999), and the activation of SSAT after transient ischemia has been indicated by increased levels of SSAT mRNA (Zoli et al, 1996).…”

Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic-pharmacodynamic modeling

“…[113][114][115] Polyamines have a number of functions in the brain, [116][117][118][119] and it is known that these endogenous compounds play an important role in excitotoxicity. 120,121 Because BBB functionality is also influenced by polyamines, a relationship among neurodegeneration, polyamines, and BBB function [122][123][124] is indicated.…”

Animal disease models generated by genetic engineering of polyamine metabolism

“…A prolonged activation of the NMDA receptor is associated with neuronal damage and a functional receptor is needed for spatial learning [65]. Taken together the results obtained with transgenic animals with greatly elevated brain putrescine, such as protection from seizure activity and ischemiareperfusion damage as well as impaired spatial learning, led us conclude that the strikingly expanded brain putrescine pools and the up to 40-fold increased molar ratio of putrescine to the higher polyamines in the transgenic animals create a partial blockade of the NMDA receptor [1].…”