MOLECULAR MEDICINE REPORTS 9: 1533-1541, 2014 Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer's disease (Review) ZHIYOU CAI Department of Neurology, The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an People's Hospital, Lu'an, Anhui 237005, P.R. China Received July 2, 2013; Accepted February 10, 2014 DOI: 10.3892/mmr.2014.2040 Abstract. Activated monoamine oxidase (MAO) has a critical 6. MAO activation contributes to cognitive impairment in role in the pathogenesis of Alzheimer's disease (AD), including patients with AD the formation of amyloid plaques from amyloid β peptide (Aβ) 7. Activated MAO contributes to the formation of amyloid production and accumulation, formation of neurofibrillary plaques tangles, and cognitive impairment via the destruction of cholin- 8. Is activated MAO associated with the formation of ergic neurons and disorder of the cholinergic system. Several neurofibrillary tangles? studies have indicated that MAO inhibitors improve cognitive 9. Evidence for the neuroprotective effect of MAO inhibitors deficits and reverse Aβ pathology by modulating proteolytic in AD cleavage of amyloid precursor protein and decreasing Aβ 10. Conclusions and outlook protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD. 1. Introduction Monoamine oxidase (MAO) catalyzes the oxidative deamina- Contents tion of biogenic and xenobiotic amines and has an important role in the metabolism of neuroactive and vasoactive amines in 1. Introduction the central nervous system (CNS) and peripheral tissues. The 2. Monoamine oxidase (MAO) enzyme preferentially degrades benzylamine and phenylethyl- 3. Involvement of MAO in neurodegeneration amine and targets a wide variety of specific neurotransmitters 4. Increased MAO activity in the platelets of patients with involved in the primary substrates of MAO in the brain, Alzheimer's disease (AD)? including epinephrine (EP), norepinephrine (NE), dopamine 5. Alterations in MAO levels in the brains of patients with (DA), serotonin (5-HT), and β-phenylethylamine (PEA) (1,2). AD The unique position of MAO in modulating the function of a diverse series of specific neurotransmitters in association with various conditions, including mood disorders (3), anxiety and depression (4,5), schizophrenia (6), attention deficit hyper- activity disorder (7-9), migraine (10), sexual maturation (11) Correspondence to: Dr Zhiyou Cai, Department of Neurology, and neurodegenerative diseases (12), has attracted significant The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an attention to the protein as a therapeutic target. People's Hospital, 21 Wanxi West Road, Lu'an, Anhui 237005, Compelling studies have shown that the involvement of P. R. Ch i na MAO in AD and neurodegenerative diseases plays an impor- E-mail: [email protected] tant role in several key pathophysiological mechanisms (13,14). MAO-B has been proposed as a biomarker, whereas activated Abbreviations: Aβ, amyloid β peptide; AD, Alzheimer's disease; MAO-B leads to cognitive dysfunction, destroys cholinergic APP, amyloid precursor protein; BACE, β-site APP cleavage neurons, causes disorder of the cholinergic system and contrib- enzyme; ChE, cholinesterase; CNS, central nervous system; utes to the formation of amyloid plaques. CSF, cerebrospinal fluid; DA, dopamine; EP, epinephrine; 5‑HT, The present review focused on evidence supporting the serotonin; MAO, monoamine oxidase; MAPK, mitogen-activated protein kinase; MMSE, Mini Mental State Examination; NE, central role that MAO has in AD pathogenesis, including the norepinephrine; NFT, neurofibrillary tangle; PD, Parkinson's formation of amyloid plaques from amyloid β peptide (Aβ) disease; PEA, β-phenylethylamine; PKC, protein kinase C production and neurofibrillary tangles (NFTs), and cognitive impairment via the destruction of cholinergic neurons and Key words: Alzheimer's disease, monoamine oxidase, disorder of the cholinergic system. Studies reporting that MAO neurodegeneration, β-amyloid, tau inhibitors improve cognitive deficits and reverse Aβ pathology by modulating proteolytic cleavage of amyloid precursor protein (APP) and decreasing Aβ protein fragments are also 1534 CAI: MONOAMINE OXIDASE INHIBITORS AS THERAPEUTIC AGENTS FOR ALZHEIMER'S DISEASE discussed. Finally, on the basis of current advances in the use of MAO inhibitors for the treatment of AD, MAO inhibitors are discussed as a promising therapeutic target for AD. 2. MAO Monoamine oxidase (EC1.4.3.4, a flavin‑containing enzyme) is widely distributed in animal tissue and catalyzes the oxidative deamination of primary amines by reaction between dioxygen and R-CH2-NH2 to form R-CHO, NH3 and H2O2 (Fig. 1). MAO Figure 1. General reaction catalyzed by MAO. The reaction of a base (R, removes an amine group by catalyzing the oxidative deamina- arbitrary group) with one ammonia and two hydrogen components plus water tion of monoamines, resulting in the corresponding aldehyde and oxygen, catalyzed by MAO, generates the aldehyde, ammonia and H2O2. and ammonia. MAO exists as two isozymes in humans: MAO, monoamine oxidase. MAO-A and MAO-B, which are distinct due to different amino acid sequences, three-dimensional structures, distribu- tions in organs and tissue, inhibitor sensitivities and substrate oxidation of monoamine substrates (18,33,34). These results specificity. The two isozymes are found in and outside the suggest that MAO is involved in the neurodegenerative patho- CNS. genesis of PD that manifests as increased oxidative stress and With regard to the functions of MAO, a wide range of a major impairment of the glutathione pathway. pathophysiological roles have been suggested, including the Studies have shown that activated MAO in the brains regulation of cardiac function and blood pressure (15), as well of patients with AD is a biomarker for AD (35-37). This as involvement in a number of psychiatric and neurological was demonstrated by [11C]-L-deprenyl using whole hemi- disorders, including mood, depression, schizophrenia, migraine, sphere autoradiography (38-40), epidemiology (41,42), sexual maturation and neurodegenerative diseases. The notable morphology (43), as well as single-photon emission computed role of MAO is in the regulation of neurotransmitter activity, tomography (44). Such studies demonstrated that: i) MAO since the primary substrates of MAO in the brain are specific activity in platelets was significantly increased in patients neurotransmitters, including EP, NE, DA, 5-HT and PEA. with AD and acted as a marker of behavioral characteristics in dementia disorders (41,45-48); ii) there were early and persis- 3. Involvement of MAO in neurodegeneration tent alterations in MAO-A and -B in the brains of patients with AD (49); iii) activated MAO led to cognitive dysfunction (50); An increasing number of studies have demonstrated the iv) activated MAO destroyed cholinergic neurons and caused involvement of MAO in neurodegenerative diseases, including disorders of the cholinergic system (51); v) activated MAO Parkinson's disease (PD) (16,17), AD (18,19), Lewy body contributed to the formation of amyloid plaques (13,14) and diseases with dementia (20) and depression (17,21). MAO is vi) activated MAO was associated with the formation of NFTs. involved in neurodegeneration via oxidative stress, which has a Pharmacological studies have demonstrated that central role in neurodegenerative diseases (22). Other mecha- MAO inhibitors exert neuroprotective effects in patients nisms have been identified, including neuroinflammation (23), with AD (21,52,53) through the following mechanisms: triggering of apoptosis (18,24), failure of aggregated-protein Improvement of cognitive impairment (50,54,55); antioxidant clearance (25-27) and glial activation (28) by MAO. and enhancement of iron chelating activities (56-59); regula- PD is the second most common age-related neurodegenera- tion of APP and Aβ expression processing (56,60), involving tive disease after AD, and is characterized by progressive loss the activation of certain signaling pathways, including the of dopaminergic neurons in the substantia nigra, depletion of p42/44 mitogen-activated protein kinase (MAPK) and protein DA in the striatum, abnormal mitochondrial and proteasomal kinase C (PKC) signaling pathways (61); and inhibition of functions and accumulation of α-synuclein (29,30). It has been cholinesterase (ChE) activity (62-64). suggested that the increased turnover of DA and dopami- nergic neurodegeneration are associated with oxidative stress 4. Increased MAO activity in the platelets of patients with derived from an increased production of hydrogen peroxide, AD? which is formed during the oxidative deamination of DA by MAO (29,31). A recent study showed that activated MAO MAO activity has previously been found to be high in the induces α-synuclein aggregation, which may be associated with brain and in platelets in patients with AD, while the activity early Parkinsonism and dopaminergic neurodegeneration in of MAO-B in the brain increases with age due to an increased the substantia nigra in SMAD family member 3-null mice (32). concentration of MAO-B (35). Compared with age- and The evidence that either inhibition or iron chelation of MAO gender-matched controls, MAO activity in platelets was signif- exerts neuroprotective effects strongly indicates that MAO is icantly higher in patients with dementia of the Alzheimer type, a major component in the process of PD neurodegeneration and the