Interrelationships between ornithine, glutamate, and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain

Daune, Genevieve; Seiler, Nikolaus

doi:10.1007/bf00971857

Cited by 34 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The value found in the present work is about twice as high as that found previously (Daune & Seiler, 1988) demonstrating the rapid and extensive inactivation of OAT by 5-FMOrn. Nevertheless, the actual rate of Orn metabolism via w)-transamination in brain may be considerably higher for the following reasons.…”

Section: Discussionsupporting

confidence: 76%

“…The rate of Orn accumulation in mouse brain has previously been determined after administration of maximum tolerable doses of gabaculine (Daune & Seiler, 1988), a compound which is an inactivator of both OAT and GABA-T (Rando & Bangerter, 1976). The value found in the present work is about twice as high as that found previously (Daune & Seiler, 1988) demonstrating the rapid and extensive inactivation of OAT by 5-FMOrn.…”

Section: Discussionsupporting

confidence: 73%

See 1 more Smart Citation

5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase

Daune¹,

Gerhart²,

Seiler³

1988

Biochemical Journal

View full text Add to dashboard Cite

5-Fluoromethylornithine (5-FMOrn) is the first specific irreversible inhibitor of L-ornithine:2-oxoacid aminotransferase (OAT) found. Single doses (greater than 10 mg/kg) of this compound inactivate OAT to a residual OAT-like activity. This activity (10-20% of total activity) is resistant to further inactivation by higher or repeated doses of 5-FMOrn, or incubation with the inactivator in vitro. Ornithine concentrations are greatly enhanced in various tissues, and urinary ornithine is dramatically increased, but no other amino acid is affected after acute treatment with 5-FMOrn. Repeated administration decreases carnosine and homocarnosine concentrations in brain. Toxic effects were not observed. The new inactivator is considered as a tool in the establishment of functions of OAT under physiological and pathological conditions.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 73%

5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase

Daune¹,

Gerhart²,

Seiler³

1988

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…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: Discussionsupporting

confidence: 62%

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

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

“…The mechanism of retinal toxicity remains undefined, although reduced ornithine aminotransferase (OAT) activity observed with VGB consumption may elevate retinal ornithine and induce a form or gyrate atrophy (De Biase et al 1991; Sorri et al 2010). Moreover, GABA is a feedback regulator of OAT (Daune and Seiler 1988). These observations suggest that monitoring ornithine levels during VGB intervention would be prudent.…”

Section: Treatment Strategies For Ssadh Deficiencymentioning

confidence: 99%

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Pearl

Theodore

et al. 2012

J of Inher Metab Disea

View full text Add to dashboard Cite

Summary This review summarizes a presentation made at the retirement Symposium of Prof. dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.

show abstract

Interrelationships between ornithine, glutamate, and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain

Cited by 34 publications

References 25 publications

5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase

5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase

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

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Contact Info

Product

Resources

About