Phenelzine: An old drug that may hold clues to the development of new neuroprotective agents

Abstract

The monoamine oxidase (MAO)-inhibiting antidepressant phenelzine (PLZ) is also used in the treatment of anxiety disorders such as panic disorder and social anxiety disorder and has been shown to have neuroprotective actions in an animal model of transient forebrain ischemia. Phenelzine has multiple actions in addition to inhibition of MAO that may contribute to its pharmacological and therapeutic profile. These actions include inhibition of GABA transaminase and elevation of brain levels of GABA, effects on functional availability of glutamate, sequestration of reactive aldehydes, inhibition of primary amine oxidase and effects on brain-derived neurotrophic factor (BDNF). 2-Phenylethylidenehydrazine (PEH) has been identified as a major metabolite of PLZ and has also been shown to elevate brain levels of GABA, to sequester reactive aldehydes and to exert neuroprotective effects in a transient forebrain ischemia model. The actions of PLZ and PEH should be considered when designing future drugs for the treatment of psychiatric and neurologic disorders, particularly those involving neurodegeneration.