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

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Abstract

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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Acknowledgements

Funds were provided by the Canadian Institutes for Health Research (CIHR), the Canada Research Chair and Canada Foundation for Innovation Programs, the Falk Institute for Molecular Therapeutics, the Davey Endowment and the Berger Fund. EMM is the recipient of an Alberta Heritage Foundation for Medical Research (AHFMR) studentship. The authors gratefully acknowledge the technical assistance of Gail Rauw.

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Authors and Affiliations

  1. Neurochemical Research Unit, Department of Psychiatry, University of Alberta, 1E7.31 Walter MacKenzie Centre, Edmonton, AB, Canada, T6G 2R7

    Erin M. MacKenzie, Suzanne L. Grant & Glen B. Baker

  2. The Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60201, USA

    Paul L. Wood

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  1. Erin M. MacKenzie
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  2. Suzanne L. Grant
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  3. Glen B. Baker
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  4. Paul L. Wood
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Correspondence to Glen B. Baker.

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MacKenzie, E.M., Grant, S.L., Baker, G.B. et al. Phenelzine Causes an Increase in Brain Ornithine that is Prevented by Prior Monoamine Oxidase Inhibition. Neurochem Res 33, 430–436 (2008). https://doi.org/10.1007/s11064-007-9448-0

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  • DOI: https://doi.org/10.1007/s11064-007-9448-0

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