Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism

Seiler, Nikolaus; Daune, Genevieve; Bolkenius, Frank N.; Knödgen, B.

doi:10.1016/0020-711x(89)90367-4

Cited by 28 publications

(22 citation statements)

References 30 publications

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“…However, inhibition of ODC alone is not likely to result in the increase in brain ORN observed in the present study, as the ODC pathway is not a significant means of ORN catabolism in the rodent brain [36]. In accordance with this, it was shown that selective inhibition of ODC in mice did not alter brain ORN levels, whereas inhibition of ORN-T alone or together with ODC resulted in a significant increase in brain ORN [34]. It is clear that further experiments are warranted to determine the effects of PLZ on the activities of ORN-T and ODC.…”

Section: Discussionsupporting

confidence: 89%

“…This is supported by the findings that GABA-T and ORN-T are closely related in terms of structure and activity [28], and that all reported GABA-T inhibitors, except for ethanolamine-O-sulfate and vigabatrin, are also inhibitors of ORN-T [28][29][30]. Furthermore, selective inhibition of ORN-T, which is heavily concentrated in nerve terminals [31], leads to accumulation of synaptic ORN [32] and drastically elevates ORN levels in the rodent brain [33,34]. It should be noted that aside from this direct effect of PLZ, ORN-T may also be indirectly inhibited by PLZ, as GABA itself is a competitive inhibitor of ORN-T, acting as part of a negative-feedback mechanism to regulate ORN-T activity in vivo [35].…”

Section: Discussionmentioning

confidence: 95%

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Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition

et al. 2007

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Phenelzine (PLZ), a nonselective irreversible inhibitor of monoamine oxidase (MAO), also inhibits GABA-transaminase (GABA-T), markedly increasing brain GABA levels. PLZ is also a substrate for MAO, and studies suggest that a metabolite formed by the action of this enzyme on PLZ may be responsible for the increase in GABA observed. We have recently found that PLZ also elevates brain ornithine (ORN), an amino acid precursor to both glutamate (and GABA) and the polyamines, and have conducted dose- and time-response studies on this effect. Rats were treated with vehicle or PLZ doses (7.5, 15 or 30 mg/kg i.p.), and brains were collected 3 h later. In the time-response study, animals were treated with vehicle or PLZ (15 mg/kg i.p.) and brains were collected 1-24 h later. To determine whether a metabolite formed by the action of MAO on PLZ may be responsible for the elevation in brain ORN observed, animals were pretreated with vehicle or the MAO inhibitor tranylcypromine (TCP) before vehicle or PLZ (15 mg/kg), and brains collected 3 h later. ORN levels (measured by an HPLC procedure) were dose- and time-dependently increased in PLZ-treated animals, with levels reaching approximately 650% of control at 6 and 12 h. Pretreatment with TCP completely abolished the PLZ-induced increase in brain ORN, suggesting, as with GABA, that a metabolite of PLZ formed by the action of MAO is responsible for the elevation of brain ORN observed. The possible contribution of increased ORN to therapeutic and/or neuroprotective properties of PLZ is discussed.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 95%

Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition

et al. 2007

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“…Furthermore, in agreement with previous results obtained in ureaseinduced hyperammonemia (Sarhan et al 1992) citrulline concentrations were significantly enhanced. It is known that the rate of putrescine formation is enhanced in brain and liver, if 5FMOrn is administered to mice (Seiler et al 1989b). It was, therefore, necessary to explore, whether the decarboxylation of ornithine to putrescine was essential or unrelated to the effect of 5FMOrn on ammonia-induced tonic convulsions.…”

Section: Resultsmentioning

confidence: 99%

“…Enhancement of putrescine formation due to elevation of ornithine concentration in brain (and other tissues) (Seiler et al 1989b) seems unimportant for the protective effect of SFMOrn, as shown by excessive treatment with the ornithine decarboxylase inhibitor 2-(difluoromethy1)ornithine DFMO. At the same time our experiments demonstrate that 2-(difluoromethy1)ornithine is not an inactivator of ornithine aminotransferase.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Endogenous Ornithine Concentrations Protect Against Tonic Seizures and Coma in Acute Ammonia Intoxication

Seiler¹,

Sarhan²,

Knoedgen³

et al. 1993

Pharmacology & Toxicology

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Pretreatment of mice with 5-fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase, diminishes the accumulation of ammonia in the brain after administration of ammonium acetate, and antagonizes ammonia-induced fatal tonic extensor convulsions. In about 50% of the treated animals the loss of the righting reflex and coma is prevented. Presumably these effects are based on the enhancement of urea formation by the increased liver ornithine concentrations. However, since brain ornithine concentrations are greatly enhanced by 5FMOrn, it is not excluded that ornithine has direct effects on cellular events involved in ammonia-induced seizure generation, even though 5FMOrn had no anticonvulsant properties in a series of established animal seizure models, including N-methyl-D,L-aspartate-induced convulsions. NMDA receptor antagonists are capable of preventing death, but do not protect against the generation of coma and tonic extensor convulsions in ammonium acetate intoxicated mice. Since no evidence was found for ammonia-induced glutamate release from rat hippocampus, there is no convincing evidence for the idea that the tonic convulsions are mediated by NMDA receptors. L-Methionine-D, L-sulfoximine (MSO)-induced seizures can be partially antagonized by pretreatment with 5FMOrn. However, the effect is considerably smaller than against ammonia-induced convulsions, although at the time of seizure onset brain ammonia levels of MSO-intoxicated mice were lower than in the animals receiving ammonium acetate. This suggests that MSO-convulsions are not entirely due to the elevation of brain ammonia concentrations, even though MSO administration mimics effects of ammonia on cortical inhibitory neuronal interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The DFMO‐induced up‐regulation of these Slcs is probably due to lowered cellular Put and Spd levels. Treatment with DFMO in vivo has been reported to have no effect on cellular levels of ornithine in various tissues making it less likely that ornithine regulates Slc3a2 and Slc7a1 expression (Seiler et al, ). On the whole, our data show that PTI‐1 (at 0.5 µM) inhibits polyamine uptake but has no effects on gene expression either for genes coding for smooth muscle contractile marker proteins or genes coding for putative polyamine transporters.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

Grossi

Phanstiel

Rippe

et al. 2015

Journal Cellular Physiology

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Increased vascular smooth muscle cell (VSMC) proliferation is a factor in atherosclerosis and injury-induced arterial (re) stenosis. Inhibition of polyamine synthesis by α-difluoro-methylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuates VSMC proliferation with high sensitivity and specificity. However, cells can escape polyamine synthesis blockade by importing polyamines from the environment. To address this issue, polyamine transport inhibitors (PTIs) have been developed. We investigated the effects of the novel trimer44NMe (PTI-1) alone and in combination with DFMO on VSMC polyamine uptake, proliferation and phenotype regulation. PTI-1 efficiently inhibited polyamine uptake in primary mouse aortic and human coronary VSMCs in the absence as well as in the presence of DFMO. Interestingly, culture with DFMO for 2 days substantially (>95%) reduced putrescine (Put) and spermidine (Spd) contents without any effect on proliferation. Culture with PTI-1 alone had no effect on either polyamine levels or proliferation rate, but the combination of both treatments reduced Put and Spd levels below the detection limit and inhibited proliferation. Treatment with DFMO for a longer time period (4 days) reduced Put and Spd below their detection limits and reduced proliferation, showing that only a small pool of polyamines is needed to sustain VSMC proliferation. Inhibited proliferation by polyamine depletion was associated with maintained expression of contractile smooth marker genes. In cultured intact mouse aorta, PTI-1 potentiated the DFMO-induced inhibition of cell proliferation. The combination of endogenous polyamine synthesis inhibition with uptake blockade is thus a viable approach for targeting unwanted vascular cell proliferation in vivo, including vascular restenosis.

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Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism

Cited by 28 publications

References 30 publications

Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition

Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition

Enhanced Endogenous Ornithine Concentrations Protect Against Tonic Seizures and Coma in Acute Ammonia Intoxication

Inhibition of Polyamine Uptake Potentiates the Anti‐Proliferative Effect of Polyamine Synthesis Inhibition and Preserves the Contractile Phenotype of Vascular Smooth Muscle Cells

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