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

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.

Advances Pertaining to the Pharmacology and Interactions of Irreversible Nonselective Monoamine Oxidase Inhibitors

“…115 The potent ability of PLZ to sequester toxic aldehydes may contribute to neuroprotective actions. 116 A PLZ metabolite produced by MAO has been proposed as the cause of GABA and alanine elevation 37 and increased brain ornithine, 117 but PLP deficiency may also be implicated.…”

Phenelzine Mitochondrial Functional Preservation and Neuroprotection after Traumatic Brain Injury Related to Scavenging of the Lipid Peroxidation-Derived Aldehyde 4-Hydroxy-2-Nonenal

“…Moreover, the idea that these two effects are mechanistically related comes partially from other studies reporting protective effects of PZ in primary neurons and astrocytes against formaldehyde-induced toxicity, 21 and some of these protective properties of PZ have been confirmed to be due to its ability to sequester aldehydes. 31 In our in vitro experiments, 4-HNE produced a concentration-dependent decrease in complex I (ADP rate) and complex II (succinate rate) oxygen consumption that was directly related to an increase in the amount of 4-HNE bound to mitochondrial proteins. In contrast, both effects were attenuated by PZ.…”

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine

“…In metabolomics studies, we also found that ip treatment of male rats with PLZ or PEH resulted in marked increases in brain cortex levels of ornithine (MacKenzie et al 2008b ) and a number of N-acetylated amino acids (Wood et al 2020 ). We speculated that the increased ornithine levels may be an indicator of decreased formation of glutamate and/or polyamines (resulting in decreased formation of reactive aldehydes such as acrolein and 3-AP), thus contributing to neuroprotection.…”