Polyamine Metabolism In Brain Research Articles

Spermine and L-Name Pretreatment Effects on Polyamine and Nitric Oxide Metabolism in Rat Brain During Seizures

Spermine and L-Name Pretreatment Effects on Polyamine and Nitric Oxide Metabolism in Rat Brain During SeizuresIn the CNS polyamines can exert opposite effects, depending on the concentration and conditions in the cell. Protective or neurotoxic polyamine effects were documented during seizures and repeated CNS excitation. Intensive research of exogenous polyamines effects during seizures induced by numerous agents did not clear up confusions about the duality of effects and the role of polyamines in seizures. In order to understand polyamine modulatory effects in seizures, the importance of NO and polyamine metabolism interdependence and the possible implication of changes of postulated NO and polyamine equillibrium in seizures, the effects of spermine alone and in combination with L-NAME (NOS inhibitor) on seizures induced by pentazol (PTZ) were investigated. To compare the obtained results, the effects of anticonvulsant midazolam on NO production during seizures were also investigated. Seizures were induced by i.p. application of pentazol (100 mg/kg b.w.). Spermine and L-NAME were administered i.p. before PTZ. In the striatum and hippocampus, spermine induced increased NO production (p<0.001) related to values in the group treated by PTZ. Application of L-NAME before spermine and PTZ caused decrease of NO production in comparison with animals treated only by PTZ or spermine and PTZ. L-NAME given before spermine exerts protective effects related to seizures induced by PTZ and to the group treated by spermine, extending the time of seizure symptoms appearance, thus confirming the NO signaling system involvement in spermine effects during seizures. Highly significant PAO activity increase caused by spermine points out the intensified interconversion of spermine into putrescine, in order to maintain the intracellular putrescine concentration. The obtained results prove a strong relationship between the NO signaling system and polyamine metabolism in the brain during seizures and the importance of their changes in this kind of CNS injury.

Reversible changes in goldfish brain polyamine concentrations and synthetic enzymes after cold exposure

Exposure of goldfish to the cold (5 °C) caused a sharp increase in brain putrescine level during the first week. Such increase continued at a minor rate for the whole period of exposure (2 months). In contrast, the content of spermidine and spermine remained unchanged. Putrescine increase was concomitant with a remarkable rise in ornithine decarboxylase activity (ODC), which reached a maximum stimulation after 1 week of cold exposure, and declined thereafter, remaining significantly higher than the control for the entire period of study. Cold exposure caused also a reduction of S-adenosylmethionine decarboxylase (AdoMetDC) activity and an increase of ornithine level, whereas methionine content was unchanged. When fish exposed to cold temperature were returned to 20 °C, the modifications observed on brain polyamine metabolism were completely reversed. Supported by previous observations, our results suggest that the changes in the polyamine metabolism induced in goldfish brain by cold exposure could represent an homeostatic mechanism carried out by the goldfish to minimize the possible effects of thermal changes.

Alzheimer's amyloid β-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity: protective effect of vitamin E

Recent evidence indicates that alterations in brain polyamine metabolism may be critical for nerve cell survival after a free radical initiated neurodegenerative process. It has been shown previously that A β(1–42) and A β(25–35) are toxic to neurons through a free radical dependent oxidative mechanism. Treatment of rat embryonic hippocampal neuronal cultures with A β-peptides increased ornithine decarboxylase (ODC) activity and spermidine uptake, suggesting that oxidative stress upregulates the polyamine mechanism for the repair of free radical damage. Pretreatment of the cells with vitamin E prior to A β exposure decreased ODC activity and spermidine uptake to control level. This study is the first to demonstrate that A β treated cells show an increased polyamine metabolism in response to free radical mediated oxidative stress and that the free radical scavenger vitamin E prevents these attenuations. These results are discussed with reference to Alzheimer's disease.

Developmental regulation of the brain polyamine-stress-response

A transient increase in brain polyamine metabolism, termed the polyamine-stress-response is a common response to stressful stimuli. Previous studies have implicated an over-reactive polyamine response as a component of the maladaptive brain response to stressful events, and as a novel molecular mechanism involved in the pathophysiology of affective disorders. Ample evidence indicates that stressful experiences during early life can alter normal developmental processes and may result in pathophysiological and behavioral changes in the adult. Additionally, an important characteristic of affective disorders is their age dependency, a phenomenon that may be correlated with a maladaptive regulation of the hypothalamic-pituitary-adrenocortical (HPA) neuroendocrine system. In the present study we measured the activities of the enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase as markers of polyamine synthesis and found that unlike adults, immature rats do not show the characteristic brain polyamine-stress-response. Instead of the characteristic increase observed in adults, ornithine decarboxylase activity in immature animals was reduced or remained unchanged (for up to 16 days of age) after a dexamethasone injection or restraint stress application. The ontogenesis of this ornithine decarboxylase response was brain region-specific, indicating its dependence on the stage of neuronal maturation. Animals treated with dexamethasone at 7 days of age, showed increased behavioral reactivity in the open-field test as adults and an attenuated increase in ornithine decarboxylase activity after a re-challenge with dexamethasone at age 60 days. The results indicate that : (1) the brain polyamine-stress-response is developmentally regulated and its ontogenesis is brain region-specific, indicating dependence on the stage of neuronal maturation ; (2) the switch to a mature polyamine-stress-response pattern coincides with the cessation of the stress hypo-responsive period in the HPA system : (3) activation of the polyamine-stress-response, as in the mature brain, appears to be a constructive reaction, while its down-regulation, as in the developing brain, may be implicated in neuronal cell death ; (4) an attenuated dexamethasone-induced increase in ornithine decarboxylase activity implicates an altered polyamine-stress-response in the maladaptive response of the brain to stressful events.

Polyamines and their metabolizing enzymes in human frontal cortex and hippocampus: Preliminary measurements in affective disorders

Affective disorders are associated with maladaptive response to stressful life events. Based on the observation that a transient increase in brain polyamine metabolism is a common response to stressful stimuli, our hypothesis is that a maladaptive polyamine stress response may be involved in the pathophysiology of affective disorders. Our current research efforts, therefore, concentrate on the characterization of this PA response, and on its pharmacological regulation. The present preliminary study is the first to measure the polyamines, putrescine, spermidine, and spermine, and their metabolizing enzymes, ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine/spermine N1 acetyltransferase, in brain autopsy samples from people who suffered from depressive disorders or schizophrenia, or from those who committed suicide. The data of affected individuals did not reveal significant differences when compared to those of suicide cases, or to those of people with no known neurologic or psychiatric abnormalities. The following regional differences were observed: spermidine concentrations and ornithine decarboxylase activity were higher, but S-adenosylmethionine decarboxylase activity was lower in the hippocampus as compared to the frontal cortex. Preliminary studies with rat brain indicate that an increase in polyamine metabolizing enzyme activities occurs within several hours after death and persists for at least 48 hours. These observations, in turn, indicate that earlier autopsies are crucial for detection of changes in polyamine metabolism. We conclude that further studies to test the polyamine hypothesis are warranted.

Accumulation of exogenous polyamines in gerbil brain after ischemia.

Regionally selective delayed neuronal degeneration is a characteristic sequel of cerebral ischemia. Recent evidence indicates that changes in brain polyamine metabolism may be critical for nerve cell survival after ischemia. Within hours after ischemia, intracellular putrescine levels are greatly increased and remain elevated for days, whereas only minor changes are noted in the levels of the polyamines spermine and spermidine. In contrast, the extracellular levels of all polyamines are low after ischemia. Injections of polyamines following ischemia, however, can protect neurons in the gerbil brain from delayed cell death, with spermine being the most potent of the polyamines. In the present study, therefore, we sought to determine if increased polyamine uptake occurs in the brain after ischemia. In the hippocampal slice preparation, temperature-dependent uptake was unique for spermine, but not for spermidine or putrescine. Uptake of [14C]spermine was transiently increased after ischemia, peaking at 150% of control by 12-13 h and subsiding by 24 h. Intravenous injections of [3H]spermidine resulted in a postischemic accumulation of this polyamine throughout the forebrain parenchyma. We conclude that: 1. Active cellular uptake of spermine is transiently increased early after ischemia; 2. A nonspecific accumulation of exogenous polyamines occurs early after ischemia probably owing to a compromised blood-brain barrier, and 3. The findings indicate that exogenous polyamines can exert their effect directly in the brain after ischemia.

Possible involvement of humoral regulation in the effects of elevated cerebral 4-aminobutyric acid levels on the polyamine metabolism in brain.

It has been reported in several recent studies that the manipulation of cerebral 4-aminobutyric acid (GABA) level results in unexpected changes in the cerebral polyamine metabolism in vivo. The mechanisms behind these interactions have remained unknown. The present results show that the changes in polyamine metabolism are not limited to the brain, but are observable also in the liver, which served as a peripheral reference tissue. Different types of responses in the activities of the polyamine-synthesizing enzymes, ornithine decarboxylase and adenosylmethionine decarboxylase, were observed after increasing the cerebral GABA concentration of mice with varying doses of two GABA transaminase inhibitors, gabaculine and ethanolamine-O-sulphate. The time course of the significant changes in the enzyme activities showed significant correlation between the brain and liver. The possibility of direct effects of the drugs on liver was excluded by injecting them intracerebroventricularly, and by performing control experiments with equal doses given peripherally. It is concluded that the observed changes in the polyamine metabolism of liver are produced through centrally mediated humoral regulation, and that the corresponding changes in the brain are obviously due to the same factor or factors, since they are significantly correlated to the changes in liver.

Developmental changes in mouse brain polyamine metabolism.

Mouse brain ornithine decarboxylase (ODC) activity is high at the time of birth, whereas S-adenosyl-L-methionine decarboxylase (SAM-DC) activity is low. ODC activity, and putrescine, spermidine and spermine concentrations decline rapidly during postnatal development to the low level characteristic of mature brains, while SAM-DC activity behaves in the opposite manner. The fluctuations in mouse brain polyamine metabolism are in accord with those found in the rat. The apparent Km values of ODC and SAM-DC for their substrates decline parallel with the decrease of substrate and product concentrations during ontogeny suggesting substrate and/or product dependent regulation of polyamine synthesis in the developing brain.

Maternal Behavior as a Regulator of Polyamine Biosynthesis in Brain and Heart of the Developing Rat Pup

Rat pups removed from the mother and placed in a warm incubator for 1 hour or more show a 50 percent reduction in ornithine decarboxylase activity in the brain and heart. The decline is not caused by lack of nutrition. Instead, these studies suggest that active maternal behavior is necessary to maintain normal polyamine metabolism in brain and heart of the pup during development.