The management of neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS), is one of the leading healthcare challenges in the fields of neurology and psychiatry. Although the aforementioned disorders appear to have different mechanisms of pathogenesis, they share a common finding of increased production of toxic reactive aldehydes in the central nervous system. These aldehydes, including acrolein, 4-hydroxy-2-nonenal, malondialdehyde, methylglyoxal, formaldehyde and 3-aminopropanal, are produced by a variety of endogenous sources including: membrane lipid peroxidation by reactive oxygen species; metabolism of monoamines and polyamines; and catalytic activity of primary amine oxidase. Reactive aldehydes can readily form adducts with nucleophilic groups in amino acids, nucleic acids and aminophospholipids, resulting in disruption of protein and cell membrane function, inhibition of DNA, RNA and protein synthesis and interference with mitochondrial pathways. There have been reports of increased aldehyde content in the cerebrospinal şuid of AD, PD and MS patients. Investigators have also reported increased aldehyde adducts in the hippocampus and adducts co-localized with neurofibrillary tangles in AD patient brains. Several in vitro studies have demonstrated that reactive aldehydes can promote formation of β-amyloid oligomers and protofibrils and induce tau phosphorylation, the major pathological hallmarks of AD. Primary amine oxidase, the enzyme responsible for production of methylglyoxal and formaldehyde, has been shown to be over-expressed and co-localized with β-amyloid deposits in cerebral blood vessels of AD patients. In PD, there are reports of increased aldehyde content and aldehyde-modified α-synuclein in the substantia nigra of patients. Interestingly, increased aldehyde content was found in the hippocampus and substantia nigra of patients exhibiting pre-clinical AD and PD pathology, respectively, suggesting that reactive aldehyde production may be an early event in the progression of these disorders. In MS patients, it was discovered that increased aldehyde content was present in oligodendrocyte-like cells in active lesions of patients. One promising strategy in treatment of these neuropsychiatric disorders is the reduction of reactive aldehyde levels in the central nervous system. Trials with antioxidant therapy have produced largely conşicting results in AD in PD, although several further investigations are now underway. While antioxidants should reduce the rate of lipid peroxidation, there are multiple additional souces of endogenous reactive aldehyde generation. Another approach may include directly sequestering the aldehydes with drugs containing nucleophilic functional groups. The sequestration of acrolein with the hydrazine drug hydralazine has been shown to be beneficial in an animal model of MS, however, these studies have not been carried out in the clinical population. We have investigated the actions of the antidepressant hydrazine drug, phenelzine and its active metabolite β-phenylethylidenehydrazine (PEH) and found that both compounds sequester the reactive aldehydes mentioned above and reduce the formation of formaldehyde from methylamine by inhibiting primary amine oxidase. The possible clinical implications of these actions of these drugs will be described. The authors are grateful to the Canadian Institutes of Health Research, the University of Alberta, the Canada Foundation for Innovation and the Queen Elizabeth II Graduate Studentship program for financial support.