Download PDF
Review  |  Open Access  |  16 Jan 2022

A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease

Views: 2752 |  Downloads: 1517 |  Cited:  1
Ageing Neur Dis 2022;2:1.
10.20517/and.2021.09 |  © The Author(s) 2022.
Author Information
Article Notes
Cite This Article


The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinson’s diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression.


Parkinson’s disease, dementia, cholinesterase, monoamine oxidase, multi-targeted drugs


With aging and the increasing life span of the population, Parkinson’s disease (PD), an age-related neurodegenerative disorder, is receiving increased attention. It is estimated that the number of PD patients will reach more than 12 million by 2040, doubling the cases seen in 2016[1]. The motor deficits of PD are emphasized in both making the initial diagnosis and in tracking the progression of the disease[2]. As understanding of the symptoms and pathogenesis deepens, however, it has been suggested that the non-motor features of PD, including cognitive impairment, i.e., dementia, should be more attended to[3,4]. A previous study indicated that approximately 25.8% of individuals with PD exhibit mild cognitive impairment[5], and longitudinal studies have documented that up to 70% of these patients will progress to dementia after ten years of symptoms[3]. In addition to cognitive impairment, other symptoms, e.g., depression, may emerge regularly throughout the development of PD[6-8], and this symptom may worsen the severity of dementia as the disease progresses. Since dementia in both Alzheimer’s disease (AD) and PD patients generally presents with similar features, present treatments for Parkinson’s disease dementia (PDD) are mostly derived from drugs utilized in AD, such as cholinesterase inhibitors (ChEIs) and memantine, which was initially developed for the treatment of AD. To date, rivastigmine is the only FDA-approved therapy that is currently licensed for PDD.

It is well known that neurodegenerative diseases, such as AD, PD, amyotrophic lateral sclerosis, and Huntington’s disease, are possibly triggered by a group of pathologies, characterized by separate etiologies with distinct morphological and pathophysiological features, including iron accumulation[9-11], generation of reactive oxygen[11] and nitrogen species[12], inflammation[13-15], mitochondrial (complex I) deficiency[16], ubiquitin-proteasome system dysfunction[17], and abnormal protein folding and aggregation[18,19]. This suggests that the “cocktail of drugs” strategy, i.e., mixing different targeted molecules as drug combinations, may offer theoretically feasible treatment for these diseases. Nonetheless, compared to using a single effective compound, the cocktail strategy increases the risk of side effects and ups the difficulty of managing drug-drug interactions, safe dosing, and metabolic shunt effects[20,21]. A single drug with multiple targets - one compound conjugating two or more diverse biological properties - thus has a pronounced advantage over single-target drugs or drug cocktails[22,23]. An attractive example of a multi-targeted drug is ladostigil (TV3326), a cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, indicated to target various pathogenic mechanisms of neurodegenerative diseases[24-27]. The underlying principle in the design of ladostigil was to join the carbamate ChE inhibitory moiety of the anti-AD drug, rivastigmine, to the irreversible selective MAO-B inhibitor, rasagiline[24]. Ladostigil has shown positive results in a phase II clinical trial evaluating its safety and efficacy in patients diagnosed with MCI[28].

Based on a similar rationale, a novel ChE-MAO inhibitor, namely MT-031 [Figure 1], was designed and synthesized for the treatment of AD. MT-031 amalgamates the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative drug, rasagiline, into the methylamino position of the ChE inhibitor, rivastigmine[29]. Since AD and PD share similar pharmacological treatment demands, this review discusses the potential use of this novel multi-targeted drug, MT-031, for dementia and depression in PD.

A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease

Figure 1. The chemical structure of the novel ChE-MAO inhibitor, MT-031[(S)-3-(1-(Methyl(prop-2-yn-1-yl)amino)ethyl)phenyl ethyl(methyl)carbamate], designed by amalgamating the active propargyl moiety of the anti-Parkinsonian drug, rasagiline, a brain selective MAO-B inhibitor, into the “N-methyl” position of the anti-AD drug ChE inhibitor, rivastigmine. AD: Alzheimer’s disease; ChE: cholinesterase; MAO: monoamine oxidase; MAO-B: monoamine oxidase-B.


Rasagiline (Azilect®) is an anti-Parkinsonian MAO-B inhibitor drug, which presented neuroprotective and neurorescue activities in animal models and neuronal cell models of neurodegeneration[30] and exerted disease-modifying effects in PD patients[30-32]. The propargyl moiety of rasagiline has been proven to be an important active functional group for its MAO inhibitory activity[33,34] and neuroprotective/neurorestorative effects[35,36]. By retaining the active propargyl moiety, the inhibition of MAO in the brain is associated with neuroprotective effects in the neurodegenerative and age-related disturbances of homeostasis, and the products of the MAO-catalyzed reaction (e.g., aldehydes and hydrogen peroxide) are compelling inducers of lipid peroxidation and the generation of free radicals in the involution of the nervous system[37,38]. By retaining the propargyl moiety of rasagiline, MT-031 was found to be a selective MAO-A inhibitor (selectivity of MAO-A/B > 500-fold, Table 1); interestingly, this is different from its parent drug, rasagiline, which is a selective MAO-B inhibitor (selectivity of MAO-B/A = 100-fold, Table 1)[29]. In humans, MAO-A is found within the outer mitochondrial membrane of both neuronal and glial cells, where it participates in the inactivation of dopamine (DA) in the primate and human brain[39]. As dopamine depletion in the striatum causes the core motor manifestations of PD, a selective MAO-A inhibitor might provide an anti-Parkinsonian benefit[40,41].

Table 1

The inhibitory effect (IC50) of MT-031 and its parent drugs, rasagiline and rivastigmine, on MAO and ChE in vitro

CompoundInhibition (IC50 μMa)
MAO-AMAO-BMAO selectivity (A/B)AChEBuChEChE selectivity (AChE/BuChE)
MT-0310.71 ± 0.04> 1000> 50058.3 ± 6.334.6 ± 8.30.59

Additionally, depression has also been reported to be one of the most common symptoms of PD, occuring in around 40% of patients with PD, and it is often persistent[42]. The efficacy of MAO-A inhibitors has been proven effective in the treatment of atypical depression, high levels of anxiety, anergic bipolar depression, and treatment-resistant depression for decades[43-45]. MAO-A mainly metabolizes serotonin (5-HT) and norepinephrine (NE), and a reduction in the 5-HT major metabolite, 5-hydroxyindoleacetic acid, in the cerebrospinal fluid was reported to be associated with violent and impulsive behavior, including violent suicide attempts[46]. The antidepressant effects of MAOIs were hypothesized to be based on a deficiency in catecholamines, specifically NE and DA, as well as possibly the indolamine 5-HT[47]; the mechanisms of action of MAOIs as antidepressants were thus thought to be because they directly resulted in increased levels of neurotransmitter amines at nerve terminals[48,49]. Selective MAO-B inhibitors may not be effective as antidepressants because MAO-B has no direct effect on either 5-HT or NE metabolism. A dual MAO-A/B inhibitor may rapidly increase DA levels to heighten feelings of pleasure, but abnormal surges in DA are linked to serious side effects[50-53]. Therefore, a drug with selective MAO-A inhibition could potentially be a safer and more effective treatment for depression in PD patients.

Moreover, an important finding is that, following administration of MT-031, there is little inhibition of MAO-A in the liver and small intestine[29,54]. Irreversible, high degrees of MAO-A inhibition in peripheral tissues is associated with potentiation of tyramine-induced cardiovascular activity[55], namely the “cheese effect”[56,57]. These data indicate that MT-031 may produce only limited potentiation of blood pressure in response to oral tyramine, as previously described for rasagiline[57,58] and other propargyl containing drugs, such as ladostigil[59], M30[60], and VAR-10303[61].


To date, acetylcholinesterase inhibitors (AChEIs) have been the mainstay of therapeutic approaches for AD. AChEIs are used to increase synaptic levels of acetylcholine (ACh) and block the breakdown of ACh by inhibiting AChE[62]. Some reports suggest that cortical cholinergic deficits are more pronounced in PDD and that they are strongly correlated with cognitive decline and neuropsychiatric disturbances in PD[63,64]. The efficacy of the only FDA approved dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine [Figure 1 and Table 1], one of the parent drugs of MT-031, has been proved in various clinical trials in the treatment of PDD[65]. Rivastigmine exerts its therapeutic effects by increasing the levels of acetylcholine in the brain via reversible inhibition of its hydrolysis[66]. It has been proposed that the effects of rivastigmine might reflect an additional property of BuChE inhibition, which is implicated in symptom progression and thus can provide some patients supplementary benefits over AChE selectivity[67]. In humans, AChE predominates (80%) and BuChE is considered to play a minor role in regulating ACh levels in the healthy brain[68]. Especially, BuChE activity rises while AChE activity remains unchanged or declines in the AD brain[68-70], thereby supporting the key role of BuChE in regulating brain acetylcholine levels[71]. Therefore, both enzymes are likely to be involved in regulating ACh levels and represent legitimate therapeutic targets to ameliorate cholinergic deficits[72]. MT-031 was found to significantly inhibit both AChE and BuChE activities in vitro, although with a lower IC50 than that of its parent drug, rivastigmine [Table 1][29]. Accordingly, our previous study showed that MT-031 treatment prevented cognitive deficits induced by scopolamine and improved spatial learning and memory. These results may be attributed to MT-031 being able attenuate scopolamine-induced ChE disturbance by inhibition of ChE activity. In addition, after acute treatment in rats, MT-031 inhibited cortical and hippocampal AChE/BuChE by 50%-70% at doses ranging from 5 to 10 mg/kg[29]. The high inhibitory effect of ChE activity is very crucial, as the fact that the clinical study of ladostigil ( in the treatment of AD did not achieve its primary outcome may be due to its low inhibitory ratio on AChE (ladostigil inhibited an average of 21.3% of AChE)[28,73]. Furthermore, 24 h after the last dose was given to mice in a chronic administration model, MT-031 still caused dose-dependent antagonism of the spatial memory deficits induced by scopolamine in mice[54]. These results may suggest that MT-031 is a reversible but long-term ChE inhibitor, and that it is able to increase brain ACh levels sufficiently to compete with scopolamine for the muscarinic receptors subserving memory[74].


One aspect of the neuroprotective activity of MT-031 is that it directly scavenges free radicals over-produced in hydrogen peroxide (H2O2)-treated SH-SY5Y cells[29]. H2O2 is a major source of free radicals; it is produced during the redox process and considered to be a messenger in intracellular signaling cascades, including cellular metabolism and proliferation[75,76]. The predominant sources of H2O2 in the brain are spontaneous superoxide dismutation catalyzed by the enzyme superoxide dismutase[77] and MAO activity[78]. MAO-A and -B, in particular, catalyze the oxidative deamination of DA, 5-HT, and NE[39] and yield metabolic products, aldehydes, and reactive oxygen species (ROS) such as H2O2. Therefore, the neuroprotective abilities of MAO inhibitors in the treatment of PD may be through reducing ROS production[39,79,80]. In addition, several lines of evidence suggest that AChE and BuChE activation may be involved in the apoptosis associated with H2O2[81,82]. The link between cholinergic signaling and oxidative stress provides an additional therapeutic target for ChEIs in PD. Indeed, the ChEls, tacrine[81], huperzine A[83], and rivastigmine[84] were demonstrated to significantly protect cells against H2O2 insult. Moreover, MT-031 was found to enhance the mRNA expression levels of neurotrophins, anti-apoptotic molecules (Bcl-2 like 1 and Bcl-2), and an anti-oxidative enzyme (catalase) in the mouse striatum, further demonstrating the significant neuroprotective and anti-oxidative actions of this drug[54]. Multiple studies with various apoptotic paradigms have shown that Bcl-2 can protect cells against oxidative insults[85-88]. Measurements of ROS levels including H2O2 have shown that Bcl-2 expression is correlated with reduced levels of oxidative stress in cells exposed to oxidative damage. Additionally, increased synaptic ACh levels resulting from AChE inhibition may potentiate the effect of neurotrophins, neuronal growth factor and brain-derived neurotrophic factor, which was previously demonstrated to induce neuroprotection against free radical insults[89,90].

Increasing evidence suggests that neuroinflammation contributes to the cascade leading to progressive neuronal damage in PD[15,91]. The major pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-2, IL-6, IL-17, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), lead to increased production of inducible oxidative stress, neuronal stress, and further neuronal dysfunction and death in the AD brain[92-95]. The anti-inflammatory effect of MT-031 was found to be associated with elevation of the levels of one of the major cytokines, IL-10, which limits inflammation by reducing the synthesis of pro-inflammatory cytokines such as IL-1, IL-6, IFN-γ, and TNF-α[54]. The anti-inflammatory effect of MT-031 was also demonstrated in proliferated splenocytes activated by anti-CD3, in which MT-031 did not affect the viability of the unstimulated splenocytes, indicating that the anti-proliferative effect was not associated with a protective effect against cytotoxicity[54]. In addition to proliferation, splenocytes and microglia cells can also be activated to produce cytokines, multi-functional soluble factors with pro- and anti-inflammatory activities[96,97]. MT-031 suppressed the elevation of IL-17 and INF-γ in anti-CD3-activated splenocytes, possibly by increasing the generation of IL-2, although the exact mechanism needs to be addressed by further study. Inconsistent with the anti-inflammatory effects seen in cell cultures, MT-031 upregulated the mRNA expression levels of the anti-inflammatory cytokine neurotrophic tyrosine kinase receptor and reduced levels of the pro-inflammatory cytokine IL-6 in a scopolamine mouse model[54].


It has been shown that scopolamine exerts its effects through antagonizing muscarinic acetylcholine receptors[98,99]. A previous study confirmed that MT-031 treatment prevented cognitive deficits induced by scopolamine and improved spatial learning and memory, as examined in the Y maze task and Morris water maze test[54]. This effect may be attributed to an increase of amine contents, NE, 5-HT, and DA, as well as to the direct effect on scopolamine-induced ChE disturbance through inhibition of ChE activity. MT-031 exerted a significant inhibitory effect on ChE in the hippocampus and frontal cortex of mice[54]. This is an advantageous property of MT-031, as previous data show that, when ChE inhibitors are less effective in the hippocampus, other brain regions may produce insufficient amounts of ACh to displace scopolamine from receptors, which results in dysfunctional mediation of working memory[100]. Our data are in line with the reported protective effects of rivastigmine[101] and ladostigil[102] in a scopolamine mouse model, suggesting the importance of inhibiting both AChE and BuChE activities in ameliorating cognitive impairments[65,101]. There are more and more studies that support the idea that multi-targeted brain selective MAO and ChE inhibitors may exert better treatment effects than single ChE inhibitors in the treatment of dementia in neurodegenerative disorders such as AD and PD[22,26,80].


Available treatments for PDD are limited in both number and quality, and they only provide symptomatic relief for cognitive impairment. The multi-factorial causes of the disease make the development of new drugs a difficult task. The rational design of incorporating two or more distinct functional pharmacophores into one molecule has been suggested to be feasible[22,103]. A single target molecule may have greater affinity towards a specific target than a molecule with multiple targets; however, a multi-target strategy creates compounds with a balanced affinity for treating the multifactorial causes of multiple neurodegenerative diseases. To date, none of the cholinesterase inhibitors in the clinic has been proved to possess neuroprotective activity or anti-depressant action. The design of the novel drug candidate, MT-031, was aimed at targeting multiple neurodegenerative processes. MT-031 is a brain selective MAO-A and AChE/BuChE inhibitor and has been found to exert a wide range of neuroprotective activities [Figure 2], including anti-oxidative activity, clearance of ROS accumulation, prevention of neuronal death, and increasing levels of neurotrophic factors. MT-031 also possesses anti-inflammatory capabilities including preventing cellular proliferation, upregulating anti-inflammatory cytokines, and downregulating pro-inflammatory cytokines[29,54]. There is evidence that MT-031 inherited the neuroprotective potency described for propargylamine derivatives in neurodegenerative animal models[29,54,104]. Similar to its other parent compound rivastigmine[101] at a dose that inhibited ChE in the cortex and hippocampus by approximately 70%, MT-031 was effective in antagonizing the working and reference memory deficits induced by scopolamine[54]. These miscellaneous pharmacological properties of MT-031 [Figure 2], accompanied by its ability to improve cognitive deficits, make this compound valuable as a novel drug candidate for the treatment of dementia and depression in PD.

A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease

Figure 2. Suggestive schematic illustration for the mechanism of multifunctional brain permeable drug, MT-031, as a potential therapeutic approach of dementia and depression in PD. PD: Parkinson’s disease; AChE: acetylcholinesterase; BuChE: butyrylcholinesterase; MAO-A: monoamine oxidase-A; ROS: reactive oxygen species; IL: interleukin; TNF-α: tumor necrosis factor-alpha; IFN-γ: interferon-gamma; TNF-α: tumor necrosis factor-alpha; Ntrk: tyrosine kinase receptor; NGF: neuronal growth factor; BDNF: brain-derived neurotrophic factor; GDNF: glial cell-derived neurotrophic factor; Bcl-2 like 1: B-cell lymphoma 2 like 1.



The authors gratefully acknowledge the support of the Rappaport Family Research Institute, Technion-Israel Institute of Technology (Haifa, Israel). The authors also thank Ms. Linda Wang for editing this manuscript.

Authors’ contributions

Wrote the review paper: Liu W

Checked the review paper: Wang Y, Youdim MBH

Availability of data and material

Not applicable.

Financial support and sponsorship

The work was supported by Youdim Pharmaceuticals.

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.


© The Author(s) 2022.


1. Dorsey ER, Elbaz A, Nichols E, et al. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018;17:939-53.

2. Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 1988;51:745-52.

3. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Mov Disord 2006;21:916-23.

4. Zečević I. Clinical practice guidelines based on evidence for cognitive-behavioural therapy in Parkinson's disease comorbidities: a literature review. Clin Psychol Psychother 2020;27:504-14.

5. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 2010;75:1062-9.

6. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord 2008;23:837-44.

7. Duncan GW, Khoo TK, Yarnall AJ, et al. Health-related quality of life in early Parkinson's disease: the impact of nonmotor symptoms. Mov Disord 2014;29:195-202.

8. Goodarzi Z, Mrklas KJ, Roberts DJ, Jette N, Pringsheim T, Holroyd-Leduc J. Detecting depression in Parkinson disease: a systematic review and meta-analysis. Neurology 2016;87:426-37.

9. Riederer P, Monoranu C, Strobel S, Iordache T, Sian-Hülsmann J. Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease. J Neural Transm (Vienna) 2021;128:1577-98.

10. Genoud S, Senior AM, Hare DJ, Double KL. Meta-analysis of copper and iron in Parkinson's disease brain and biofluids. Mov Disord 2020;35:662-71.

11. Van Houten B, Woshner V, Santos JH. Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst) 2006;5:145-52.

12. Liguori I, Russo G, Curcio F, et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018;13:757-72.

13. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016;353:777-83.

14. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology 2018;154:204-19.

15. Hirsch EC, Standaert DG. Ten unsolved questions about neuroinflammation in Parkinson's disease. Mov Disord 2021;36:16-24.

16. de Moura MB, dos Santos LS, Van Houten B. Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 2010;51:391-405.

17. Paul S. Dysfunction of the ubiquitin-proteasome system in multiple disease conditions: therapeutic approaches. Bioessays 2008;30:1172-84.

18. Dobson CM. Protein aggregation and its consequences for human disease. Protein Pept Lett 2006;13:219-27.

19. Chiti F, Dobson CM. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 2017;86:27-68.

20. Hopkins AL, Mason JS, Overington JP. Can we rationally design promiscuous drugs? Curr Opin Struct Biol 2006;16:127-36.

21. Savelieff MG, Nam G, Kang J, Lee HJ, Lee M, Lim MH. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in the last decade. Chem Rev 2019;119:1221-322.

22. Youdim MB. Why do we need multifunctional neuroprotective and neurorestorative drugs for Parkinson's and Alzheimer's diseases as disease modifying agents. Exp Neurobiol 2010;19:1-14.

23. Van der Schyf CJ, Geldenhuys WJ. Multimodal drugs and their future for Alzheimer's and Parkinson's disease. Int Rev Neurobiol 2011;100:107-25.

24. Weinstock M, Bejar C, Wang R, et al. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. In: Riederer P, Calne DB, Horowski R, Mizuno Y, Olanow CW, Poewe W, Youdim MBH, editors. Advances in Research on Neurodegeneration. Vienna: Springer; 2000. p. 157-69.

25. Weinstock M, Poltyrev T, Bejar C, Youdim MB. Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacology (Berl) 2002;160:318-24.

26. Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. Curr Drug Targets 2012;13:483-94.

27. Weinstock M, Bejar C, Schorer-Apelbaum D, Panarsky R, Luques L, Shoham S. Dose-dependent effects of ladostigil on microglial activation and cognition in aged rats. J Neuroimmune Pharmacol 2013;8:345-55.

28. Schneider LS, Geffen Y, Rabinowitz J, et al. Ladostigil Study Group. Low-dose ladostigil for mild cognitive impairment: a phase 2 placebo-controlled clinical trial. Neurology 2019;93:e1474-84.

29. Liu W, Lang M, Youdim MBH, et al. Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease. Neuropharmacology 2016;109:376-85.

30. Youdim MB, Bar Am O, Yogev-Falach M, et al. Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res 2005;79:172-9.

31. Olanow CW, Rascol O, Hauser R, et al. ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009;361:1268-78.

32. Hauser RA, Li R, Pérez A, et al. NINDS NET-PD Investigators. Longer duration of MAO-B inhibitor exposure is associated with less clinical decline in Parkinson's disease: an analysis of NET-PD LS1. J Parkinsons Dis 2017;7:117-27.

33. Knoll J. [History of deprenyl--the first selective inhibitor of monoamine oxidase type B]. Vopr Med Khim 1997;43:482-93.

34. Youdim MB. Rasagiline: an anti-Parkinson drug with neuroprotective activity. Expert Rev Neurother 2003;3:737-49.

35. Weinreb O, Amit T, Bar-Am O, Chillag-Talmor O, Youdim MB. Novel neuroprotective mechanism of action of rasagiline is associated with its propargyl moiety: interaction of Bcl-2 family members with PKC pathway. Ann N Y Acad Sci 2005;1053:348-55.

36. Weinreb O, Amit T, Bar-am O, Sagi Y, Mandel S, Youdim MBH.

37. Kumar MJ, Andersen JK. Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol 2004;30:77-90.

38. Shemyakov SE. Monoamine oxidase activity, lipid peroxidation, and morphological changes in human hypothalamus during aging. Bull Exp Biol Med 2001;131:586-8.

39. Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006;7:295-309.

40. Huot P. Monoamine oxidase A inhibition and Parkinson's disease. Neurodegener Dis Manag 2020;10:335-7.

41. Hamadjida A, Nuara SG, Frouni I, et al. Monoamine oxidase A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset. Naunyn Schmiedebergs Arch Pharmacol 2020;393:2139-44.

42. van der Hoek TC, Bus BA, Matui P, van der Marck MA, Esselink RA, Tendolkar I. Prevalence of depression in Parkinson's disease: effects of disease stage, motor subtype and gender. J Neurol Sci 2011;310:220-4.

43. Meyer JH, Wilson AA, Sagrati S, et al. Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 2009;66:1304-12.

44. Sacher J, Wilson AA, Houle S, et al. Elevated brain monoamine oxidase A binding in the early postpartum period. Arch Gen Psychiatry 2010;67:468-74.

45. Sacher J, Houle S, Parkes J, et al. Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: an [11C]-harmine PET study. J Psychiatry Neurosci 2011;36:375-82.

46. Mann JJ, Currier D. Medication in suicide prevention insights from neurobiology of suicidal behavior. In: Dwivedi Y, editor. The neurobiological basis of suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012.

47. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965;122:509-22.

48. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990;47:411-8.

49. Bymaster FP, McNamara RK, Tran PV. New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opin Investig Drugs 2003;12:531-43.

50. Lacombe S, Stanislav SW, Marken PA. Pharmacologic treatment of cocaine abuse. DICP 1991;25:818-23.

51. Miczek KA, Haney M. Psychomotor stimulant effects of d-amphetamine, MDMA and PCP: aggressive and schedule-controlled behavior in mice. Psychopharmacology (Berl) 1994;115:358-65.

52. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with parkinsonism and anti-Parkinson drugs. Calcif Tissue Int 2007;81:153-61.

53. Krzymowski T, Stefanczyk-Krzymowska S. New facts and the concept of physiological regulation of the dopaminergic system function and its disorders. J Physiol Pharmacol 2015;66:331-41.

54. Liu W, Rabinovich A, Nash Y, et al. Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells. Neuropharmacology 2017;113:445-56.

55. Monoamine oxidase inhibitors. Meyler's side effects of drugs: the international encyclopedia of adverse drug reactions and interactions. Elsevier; 2006. p. 2371-8.

56. Finberg JP, Tenne M. Relationship between tyramine potentiation and selective inhibition of monoamine oxidase types A and B in the rat vas deferens. Br J Pharmacol 1982;77:13-21.

57. Rudzik AD, Eble JN. The potentiation of pressor responses to tyramine by a number of amphetamine-like compounds. Proc Soc Exp Biol Med 1967;124:655-7.

58. Finberg JP, Lamensdorf I, Weinstock M, Schwartz M, Youdim MB. Pharmacology of rasagiline (N-propargyl-1R-aminoindan). Adv Neurol 1999;80:495-9.

59. Weinstock M, Gorodetsky E, Wang R, Gross A, Weinreb O, Youdim M. Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits11Supported by Teva Pharmaceuticals Ltd (Israel). Neuropharmacology 2002;43:999-1005.

60. Gal S, Abassi ZA, Youdim MB. Limited potentiation of blood pressure in response to oral tyramine by the anti-Parkinson brain selective multifunctional monoamine oxidase-AB inhibitor, M30. Neurotox Res 2010;18:143-50.

61. Bar-Am O, Amit T, Kupershmidt L, et al. Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging. Neurobiol Aging 2015;36:1529-42.

62. Tabet N. Acetylcholinesterase inhibitors for Alzheimer's disease: anti-inflammatories in acetylcholine clothing! Age Ageing 2006;35:336-8.

63. Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60:1745-8.

64. Hilker R, Thomas AV, Klein JC, et al. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology 2005;65:1716-22.

65. Kandiah N, Pai MC, Senanarong V, et al. Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia. Clin Interv Aging 2017;12:697-707.

66. Weinstock M. Selectivity of cholinesterase inhibition: clinical implications for the treatment of Alzheimer's disease. CNS Drugs 1999;12:307-23.

67. Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler NR. Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit. J Neural Transm (Vienna) 2002;109:1053-65.

68. Mesulam M, Guillozet A, Shaw P, Quinn B. Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 2002;9:88-93.

69. Perry EK, Perry RH, Blessed G, Tomlinson BE. Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 1978;4:273-7.

70. Mesulam M, Guillozet A, Shaw P, Levey A, Duysen E, Lockridge O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002;110:627-39.

71. Greig NH, Utsuki T, Yu Q, et al. A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase. Curr Med Res Opin 2001;17:159-65.

72. Nordberg A, Ballard C, Bullock R, Darreh-Shori T, Somogyi M. A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. Prim Care Companion CNS Disord 2013;15:PCC.

73. Darreh-Shori T, Almkvist O, Guan ZZ, et al. Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology 2002;59:563-72.

74. Müller T. Rivastigmine in the treatment of patients with Alzheimer's disease. Neuropsychiatr Dis Treat 2007;3:211-8.

75. Rhee SG. Redox signaling: hydrogen peroxide as intracellular messenger. Exp Mol Med 1999;31:53-9.

76. Stone JR, Yang S. Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 2006;8:243-70.

77. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995;64:97-112.

78. Nicotra A. Monoamine oxidase expression during development and aging. NeuroToxicology 2004;25:155-65.

79. Riederer P. Monoamine oxidase-B inhibition in Alzheimer's disease. NeuroToxicology 2004;25:271-7.

80. Youdim MB, Buccafusco JJ. CNS targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases. J Neural Transm (Vienna) 2005;112:519-37.

81. Xiao XQ, Lee NT, Carlier PR, Pang Y, Han YF. Bis(7)-tacrine, a promising anti-Alzheimer's agent, reduces hydrogen peroxide-induced injury in rat pheochromocytoma cells: comparison with tacrine. Neuroscience Letters 2000;290:197-200.

82. Schallreuter KU, Elwary S. Hydrogen peroxide regulates the cholinergic signal in a concentration dependent manner. Life Sci 2007;80:2221-6.

83. Xiao XQ, Yang JW, Tang XC. Huperzine A protects rat pheochromocytoma cells against hydrogen peroxide-induced injury. Neurosci Lett 1999;275:73-6.

84. Mortazavian SM, Parsaee H, Mousavi SH, Tayarani-Najaran Z, Ghorbani A, Sadeghnia HR. Acetylcholinesterase inhibitors promote angiogenesis in chick chorioallantoic membrane and inhibit apoptosis of endothelial cells. Int J Alzheimers Dis 2013;2013:121068.

85. Tyurina YY, Tyurin VA, Carta G, Quinn PJ, Schor NF, Kagan VE. Direct evidence for antioxidant effect of Bcl-2 in PC12 rat pheochromocytoma cells. Arch Biochem Biophys 1997;344:413-23.

86. Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 2001;78:727-35.

87. Godley BF, Jin GF, Guo YS, Hurst JS. Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H(2)O(2). Exp Eye Res 2002;74:663-9.

88. Tran VV, Chen G, Newgard CB, Hohmeier HE. Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. Diabetes 2003;52:1423-32.

89. Jackson GR, Apffel L, Werrbach-Perez K, Perez-Polo JR. Role of nerve growth factor in oxidant-antioxidant balance and neuronal injury. I. Stimulation of hydrogen peroxide resistance. J Neurosci Res 1990;25:360-8.

90. Mattson MP, Lovell MA, Furukawa K, Markesbery WR. Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 1995;65:1740-51.

91. Hirsch EC, Hunot S, Hartmann A. Neuroinflammatory processes in Parkinson's disease. Parkinsonism Relat Disord 2005;11 Suppl 1:S9-S15.

92. Clark BD, Collins KL, Gandy MS, Webb AC, Auron PE. Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene. Nucleic Acids Res 1986;14:7897-914.

93. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013;25:469-84.

94. Zhang YY, Fan YC, Wang M, Wang D, Li XH. Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer's disease. Clin Interv Aging 2013;8:103-10.

95. Jabbari Azad F, Talaei A, Rafatpanah H, Yousefzadeh H, Jafari R, et al. Association between Cytokine production and disease severity in Alzheimer's disease. Iran J Allergy Asthma Immunol 2014;13:433-9.

96. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci 1997;2:d12-26.

97. Feng LL, Wu XF, Liu HL, et al. Vaticaffinol, a resveratrol tetramer, exerts more preferable immunosuppressive activity than its precursor in vitro and in vivo through multiple aspects against activated T lymphocytes. Toxicol Appl Pharmacol 2013;267:167-73.

98. Henderson Z, Sherriff FE. Distribution of choline acetyltransferase immunoreactive axons and terminals in the rat and ferret brainstem. J Comp Neurol 1991;314:147-63.

99. Mahmoodi G, Ahmadi S, Pourmotabbed A, Oryan S, Zarrindast MR. Inhibitory avoidance memory deficit induced by scopolamine: interaction of cholinergic and glutamatergic systems in the ventral tegmental area. Neurobiol Learn Mem 2010;94:83-90.

100. Nielsen JA, Mena E, Williams IH, Nocerini MR, Liston D. Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes. Eur J Pharmacol 1989;173:53-64.

101. Bejar C, Wang R, Weinstock M. Effect of rivastigmine on scopolamine-induced memory impairment in rats. Eur J Pharmacol 1999;383:231-40.

102. Weinstock M, Gorodetsky E, Poltyrev T, Gross A, Sagi Y, Youdim M. A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:555-61.

103. Buccafusco JJ, Terry AV Jr. Multiple central nervous system targets for eliciting beneficial effects on memory and cognition. J Pharmacol Exp Ther 2000;295:438-46.

104. Bar-Am O, Amit T, Youdim MB, Weinreb O. Neuroprotective and neurorestorative potential of propargylamine derivatives in ageing: focus on mitochondrial targets. J Neural Transm (Vienna) 2016;123:125-35.

Cite This Article

Export citation file: BibTeX | EndNote | RIS

OAE Style

Liu W, Wang Y, Youdim MBH. A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease. Ageing Neur Dis 2022;2:1.

AMA Style

Liu W, Wang Y, Youdim MBH. A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease. Ageing and Neurodegenerative Diseases. 2022; 2(1): 1.

Chicago/Turabian Style

Wei Liu, Yuqiang Wang, Moussa B. H. Youdim. 2022. "A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease" Ageing and Neurodegenerative Diseases. 2, no.1: 1.

ACS Style

Liu, W.; Wang Y.; Youdim MBH. A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson's disease. Ageing. Neur. Dis. 2022, 2, 1.

About This Article

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments




Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at

Download PDF
Share This Article
Scan the QR code for reading!
See Updates
Ageing and Neurodegenerative Diseases
ISSN 2769-5301 (Online)


All published articles will be preserved here permanently:


All published articles will be preserved here permanently: