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Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neurons from cell death in cellular and animal models. Suppression of mitochondrial membrane permeabilization and subsequent activation of apoptosis cascade, and induction of anti-apoptotic, pro-survival genes are proposed to contribute the anti-apoptotic function. Rasagiline suppresses neurotoxin- and oxidative stress-induced membrane permeabilization in isolated mitochondria, but the mechanism has been not fully clarified. In this paper, regulation of the mitochondrial permeability transition pore by rasagiline and selegiline was examined in apoptosis induced by PK11195, a ligand of the outer membrane translocator protein 18 kDa (TSPO) in SH-SY5Y cells. The pore opening was quantitatively measured using a simultaneous monitoring system for calcium (Ca) and superoxide (O) (Ishibashi et al. in Biochem Biophys Res Commun 344:571-580, ). The association of the pore opening with Ca efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca was correlated with the cytotoxicity of TSPO antagonists, PK11195, FGIN-1-27 and protoporphyrin IX, whereas a TSPO agonist, 4-chloro-diazepamine, did not significantly increase Ca or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca efflux through the mitochondrial permeability transition pore dose dependently. Ca efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed. [ABSTRACT FROM AUTHOR]

Type B monoamine oxidase (MAO-B) is proposed to be involved in the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, through oxidative stress and synthesis of neurotoxins. MAO-B inhibitors, rasagiline and selegiline [(−)deprenyl], protect neuronal cells by direct intervention in mitochondrial death signaling and induction of pro-survival Bcl-2 and neurotrophic factors. Recently, type A MAO (MAO-A) was found to mediate the induction of anti-apoptotic Bcl-2 by rasagiline, whereas MAO-A increases in neuronal death and also serves as a target of neurotoxins. These controversial results suggest that MAO-A may play a decisive role in neuronal survival and death. This paper reports that rasagiline and selegiline increased the mRNA, protein and catalytic activity of MAO-A in SH-SY5Y cells. Silencing MAO- A expression with small interfering (si)RNA suppressed rasagiline-dependent MAO- A expression, but MAO-B overexpression in SH-SY5Y cells did not affect, suggesting that MAO-A, not MAO-B, might be associated with MAO-A upregulation. Rasagiline reduced R1, a MAO-A specific repressor, but selegiline did not. Mithramycin-A, an inhibitor of Sp1 binding, and actinomycin-D, a transcriptional inhibitor, reduced the rasagiline-dependent upregulation of MAO- A mRNA, indicating that rasagiline induced MAO- A transcriptionally through R1-Sp1 pathway, whereas selegiline by another non-defined pathway. These results are discussed in relation to the role of MAO-A and these MAO-B inhibitors in neuronal death and neuroprotection. [ABSTRACT FROM AUTHOR]

Abstract: In this article, the effects of allicin, a biological active compound of garlic, on HL60 and U937 cell lines were examined. Allicin induced growth inhibition and elicited apoptotic events such as blebbing, mitochondrial membrane depolarization, cytochrome c release into the cytosol, activation of caspase 9 and caspase 3 and DNA fragmentation. Pretreatment of HL60 cells with cyclosporine A, an inhibitor of the mitochondrial permeability transition pore (mPTP), inhibited allicin-treated cell death. HL60 cell survival after 1 h pretreatment with cyclosporine A, followed by 16 h in presence of allicin (5 μM) was ∼80% compared to allicin treatment alone (∼50%). Also N-acetyl cysteine, a reduced glutathione (GSH) precursor, prevented cell death. The effects of cyclosporine A and N-acetyl cysteine suggest the involvement of mPTP and intracellular GSH level in the cytotoxicity. Indeed, allicin depleted GSH in the cytosol and mitochondria, and buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly augmented allicin-induced apoptosis. In HL60 cells treated with allicin (5 μM, 30 min) the redox state for 2GSH/oxidized glutathione shifted from E GSH −240  to −170 mV. The same shift was observed in U937 cells treated with allicin at a higher concentration for a longer period of incubation (20 μM, 2 h). The apoptotic events induced by various concentrations of allicin correlate to intracellular GSH levels in the two cell types tested (HL60: 3.7 nmol/106 cells; U937: 7.7 nmol/106 cells). The emerging mechanistic basis for the antiproliferative function of allicin, therefore, involves the activation of the mitochondrial apoptotic pathway by GSH depletion and by changes in the intracellular redox status. [Copyright &y& Elsevier]

R-(−)-1-(Benzofuran-2-yl)-2-propylaminopentane HCl [R-(−)-BPAP] is one of “catecholaminergic and serotonergic enhancers“, which were proposed to improve symptoms through increase in impulse-evoked release of monoamine neurotransmitters for Parkinson''s disease. It was reported that (−)-BPAP up-regulated the synthesis of neurotrophic factors in mouse astrocytes, suggesting the neuroprotective potency of (−)-BPAP. In this paper, the neuroprotective function of (−)-BPAP and the related compounds was examined against apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], a possible pathogenic toxin in Parkinson''s disease, in human dopaminergic neuroblastoma SH-SY5Y cells. The anti-apoptotic activity was confirmed with some of (−)-BPAP analogues, and the mechanism was found to be due to the direct stabilization of mitochondrial membrane potential and the induction of anti-apoptotic Bcl-2. The studies on structure-activity relationship demonstrated that the potency to stabilize the mitochondrial membrane potential depended on the absolute stereo-chemical structure of BPAP derivatives. The compounds with dextrorotation prevented the mitochondrial permeability transition, whereas those with levorotation did not. The presence of a propargyl or propyl group at the amino residue of R-(−)-1-(benzofuran-2-yl)-2-propylamine increased potency to stabilize the membrane potential and prevent apoptosis. R-FPFS-1169 and R-FPFS-1180 had more potent to induce Bcl-2 and prevent apoptosis than the corresponding S-enantiomers. These results are discussed with the possible application of BPAP derivatives as neuroprotective agents in Parkinson''s disease and other neurodegenerative disorders. [Copyright &y& Elsevier]

N-Propargyl-l(R)-aminoindan, rasagiline, an anti-Parkinson drug, was found to increase the protein and mRNA levels of glial cell line-derived neurotrophic factor (GDNF) in human neuroblastoma SH-SY5Y cells, whereas an analogue without a propargyl residue, aminoindan, did not. GDNF is known to protect dopaminergic neurons in animal and cellular models of Parkinson’s disease, and the supplement has been tried for the treatment of degenerating dopamine neurons in Parkinsonian patients. In this paper, intracellular mechanism underlying the induction of GDNF was studied. Rasagiline induced phosphorylation of inhibitory subunit (IκB) of nuclear factor-κB (NF-κB), and translocation of active p65 subunit from cytoplasm into nuclei. Activation of NF-κB was also quantitatively determined by NF-κB p65 transcription assay. Sulfasalazine, an inhibitor of IκB kinase, suppressed the activation of NF-κB and the increase of GDNF by rasagiline simultaneously, further indicating the involvement of the IκB kinase-NF-κB pathway. The results on the activation of the transcription factor by rasagiline are discussed in relation to its possible application as a neuroprotective drug to halt declining of neurons in neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. [Copyright &y& Elsevier]

In Parkinson''s disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (−)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. [Copyright &y& Elsevier]

Carbon capture and storage (CCS) is a promising method for mitigating the greenhouse effect. If we could utilize carbon dioxide (CO 2) for recovery of geothermal energy and shale gas, CCS will be much more eagerly developed and adopted by compensating its cost. We clarified that hydraulic fracturing (HF) using CO 2 tended to induce three-dimensionally sinuous cracks with many secondary branches, which appear to be desirable pathways for energy recovery. However, in a laboratory experiment, it was difficult to evaluate crack extension size and effects of macroscopic pre-existing cracks. Thus, we conducted a HF experiment using CO 2 in a hole 10 m long that was drilled in a hot rock mass, thus satisfying the temperature necessary to form supercritical (SC) CO 2. A bi-wing crack 3.33 m in length was induced along the hole; this crack was significantly larger than the approximately 0.5 m long crack we made with water at another site. The fact that acoustic emission (AE) hypocenters distributed in almost perpendicular to an initial HF crack direction without pressure suggested that CO 2 could easily intrude and enhance AE occurrence along a pre-existing crack. Focal mechanisms using P wave first-motion polarities elucidated that many compression-dominant AE events were recorded; these were never observed in similar HF experiment we conducted using water. The compression-dominant events were probably induced by crack closure due to the degassing of injected CO 2. Even if CO 2 injection induces many AE events, the compressive-dominant events out of them unlikely trigger natural earthquakes because they never create new cracks. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by its distinct pathological features; loss of dopamine neurons in the substantia nigra pars compacta and accumulation of Lewy bodies and Lewy neurites containing modified α-synuclein. Beneficial effects of L-DOPA and dopamine replacement therapy indicate dopamine deficit as one of the main pathogenic factors. Dopamine and its oxidation products are proposed to induce selective vulnerability in dopamine neurons. However, Parkinson's disease is now considered as a generalized disease with dysfunction of several neurotransmitter systems caused by multiple genetic and environmental factors. The pathogenic factors include oxidative stress, mitochondrial dysfunction, α-synuclein accumulation, programmed cell death, impaired proteolytic systems, neuroinflammation, and decline of neurotrophic factors. This paper presents interactions among dopamine, α-synuclein, monoamine oxidase, its inhibitors, and related genes in mitochondria. α-Synuclein inhibits dopamine synthesis and function. Vice versa, dopamine oxidation by monoamine oxidase produces toxic aldehydes, reactive oxygen species, and quinones, which modify α-synuclein, and promote its fibril production and accumulation in mitochondria. Excessive dopamine in experimental models modifies proteins in the mitochondrial electron transport chain and inhibits the function. α-Synuclein and familiar Parkinson's disease-related gene products modify the expression and activity of monoamine oxidase. Type A monoamine oxidase is associated with neuroprotection by an unspecific dose of inhibitors of type B monoamine oxidase, rasagiline and selegiline. Rasagiline and selegiline prevent α-synuclein fibrillization, modulate this toxic collaboration, and exert neuroprotection in experimental studies. Complex interactions between these pathogenic factors play a decisive role in neurodegeneration in PD and should be further defined to develop new therapies for Parkinson's disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.

Parkinson's disease is characterized by typical motor symptoms, loss of dopamine neurons in the substantia nigra, and accumulation of Lewy body composed of mutated α-synuclein. However, now it is considered as a generalized disease with multiple pathological features. Present available treatments can ameliorate symptoms at least for a while, but only a few therapies could delay progressive neurodegeneration of dopamine neurons. Lewy body accumulates in peripheral tissues many years before motor dysfunction becomes manifest, suggesting that disease-modifying therapy should start earlier during the premotor stage. Long-termed regulation of lifestyle, diet and supplement of nutraceuticals may be possible ways for the disease-modification. Diet can reduce the incidence of Parkinson's disease and phytochemicals, major bioactive ingredients of herbs and plant food, modulate multiple pathogenic factors and exert neuroprotective effects in preclinical studies. This review presents mechanisms underlying neuroprotection of phytochemicals against neuronal cell death and α-synuclein toxicity in Parkinson's disease. Phytochemicals are antioxidants, maintain mitochondrial function and homeostasis, prevent intrinsic apoptosis and neuroinflammation, activate cellular signal pathways to induce anti-apoptotic and pro-survival genes, such as Bcl-2 protein family and neurotrophic factors, and promote cleavage of damaged mitochondria and α-synuclein aggregates. Phytochemicals prevent α-synuclein oligomerization and aggregation, and dissolve preformed α-synuclein aggregates. Novel neuroprotective agents are expected to develop based on the scaffold of phytochemicals permeable across the blood-brain-barrier, to increase the bioavailability, ameliorate brain dysfunction and prevent neurodegeneration., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Parkinson's disease has been considered as a motor neuron disease with dopamine (DA) deficit caused by neuronal loss in the substantia nigra, but now proposed as a multi-system disorder associated with α-synuclein accumulation in neuronal and non-neuronal systems. Neuroprotection in Parkinson's disease has intended to halt or reverse cell death of nigro-striatal DA neurons and prevent the disease progression, but clinical studies have not presented enough beneficial results, except the trial of rasagiline by delayed start design at low dose of 1 mg/day only. Now strategy of disease-modifying therapy should be reconsidered taking consideration of accumulation and toxicity of α-synuclein preceding the manifest of motor symptoms. Hitherto neuroprotective therapy has been aimed to mitigate non-specific risk factors; oxidative stress, mitochondrial dysfunction, apoptosis, deficits of neurotrophic factors (NTFs), inflammation and accumulation of pathogenic protein. Future disease-modify therapy should target more specified pathogenic factors, including deregulated mitochondrial homeostasis, deficit of NTFs and α-synuclein toxicity. Selegiline and rasagiline, inhibitors of type B monoamine oxidase, have been proved to exhibit potent neuroprotective function: regulation of mitochondrial apoptosis system, maintenance of mitochondrial function, increased expression of genes coding antioxidant enzymes, anti-apoptotic Bcl-2 and pro-survival NTFs, and suppression of oligomerization and aggregation of α-synuclein and the toxicity in cellular and animal experiments. However, the present available pharmacological therapy starts too late to reverse disease progression, and future disease-modifying therapy should include also non-pharmacological complementary therapy during the prodromal stage.

Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. This review presents a novel role of MAO-A and B, their substrates and inhibitors, and hydrogen peroxide in brain function and neuronal survival and death. MAO-A activity is regulated not only by genetic factor, but also by environmental factors, including stress, hormonal deregulation, and food factors. MAO-A activity fluctuates by genetic-environmental factors, modulates the neuronal response to the stimuli, and affects behavior and emotional activities. MAO-B inhibitors selegiline and rasagiline protect neurons via increase expression of anti-apoptotic Bcl-2 and pro-survival neurotrophic factors in human neuroblastoma SH-SY5Y and glioblastoma U118MG cell lines. MAO-A knockdown suppressed the rasagiline-induced gene expression in SH-SY5Y cells, whereas MAO-B silencing enhanced the basal- and selegiline-induced gene expression in U118MG cells. MAO-A and B were shown to function as a mediator or repressor of gene expression, respectively. Further study on cellular mechanism underlying regulation of signal pathways by MAO-A and B may bring us a new insight on the role of MAOs in decision of neuronal fate and the development of novel therapeutic strategy may be expected for neuropsychiatric disorders.

Recently, toxic α-synuclein oligomer, which can mediate cell-to-cell propagation is suggested to cause sporadic Parkinson disease. α-Synuclein interacts with membrane lipids especially polyunsaturated fatty acids to stabilize its three-dementional structure. Peroxidation of polyunsaturated fatty acids may reduce their affinity to α-synuclein and peroxidation byproducts might modify α-synuclein. 4-Hydroxy-2-nonenal derived from n -6 polyunsaturated fatty acids was reported to modify α-synuclein to produce a toxic oligomer. Moreover, the accumulation of 4-hydroxy-2-nonenal, which could induce oligomeriztion of α-synuclein, was found in parkinsonian brains. Docosahexaenoic acid, an n -3 polyunsaturated fatty acids abundant in the neuronal membrane, was also found to enhance α-synuclein oligomerization; however, the precise details of the chemical reaction involved are unclear. Propanoylated lysine, a specific indicator of docosahexaenoic acid oxidation, was increased in neuronal differentiated human neuroblastoma SH-SY5Y cells overexpressing α-synuclein. α-Synuclein might be modified by the peroxidation products and then, is degraded by the autophagy-lysosome system. In addition, in the cells overexpressing α-synuclein, the mitochondrial electrone transfer chain was found to be inhibited. Accumulation of abnormal α-synuclein modified by lipid radicals derived from polyunsaturated fatty acids may be not only an indicator of brain oxidative stress but also causative of neurodegeneration such as Parkinson disease by impairing mitochondrial function., Competing Interests: No potential conflicts of interest were disclosed.

Bioactive compounds in food and beverages have been reported to promote health and prevent age-associated decline in cognitive, motor and sensory activities, and emotional function. Phytochemicals, a ubiquitous class of plant secondary metabolites, protect neuronal cells by interaction with cellular activities, in addition to the antioxidant and anti-inflammatory function. In aging and age-associated neurodegenerative disorders, phytochemicals protect neuronal cells by neurotrophic factor-mimic activity, in addition to suppression of apoptosis signaling in mitochondria. This review presents the cellular mechanisms underlying anti-apoptotic function and neurotrophic function of phytochemicals in the brain. Phytochemicals bind to receptors of neurotrophic factors, and also receptors for γ-aminobutyric acid, acetylcholine, serotonin, and glutamate and estrogen, and activate downstream signal pathways. Phytochemicals also directly intervene intracellular signaling molecules to modify the brain function. Finally, phytochemicals enhance the endogenous biosynthesis of genes coding anti-apoptotic Bcl-2 and neurotrophic factors, such as brain-derived and glial cell line-derived neurotrophic factor. The gene induction may play a major role in the neuroprotective function of dietary compounds shown by epidemiological studies. Quantitative measurement of neurotrophic factors induced by phytochemicals in the serum, cerebrospinal fluid, and other clinical samples is proposed as a surrogate assay method to evaluate the neuroprotective potency. Development of novel neuroprotective compounds is expected among compounds chemically synthesized from the brain-permeable basic structure of phytochemicals.

Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinson's and Alzheimer's diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the "type-specificity" of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death.

Nervous system controls all the organs in the living like a symphony. In this chapter, the mechanism of neuronal death in aged is discussed in relation to oxidative stress. Polyunsaturated fatty acid (PUFA) is known to be rich in the membranous component of the neurons and plays an important role in maintaining the neuronal functions. Recent reports revealed that oxidation of omega-3 and omega-6 PUFAs, such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), are potent antioxidant but simultaneously, their oxidation products are potentially toxic. In this chapter, the existence of early oxidation products of PUFA is examined in the samples from neurodegenerative disorders and the cellular model. Accumulation of proteins with abnormal conformation is suggested to induce neuronal death by disturbance of proteolysis and mitochondrial function. The role of lipid peroxide and lipid-derived aldehyde adduct proteins is discussed in relation to brain ageing and age-related neurodegeneration.

Rasagiline protects neuronal cells from cell death caused by various lines of insults. Its neuroprotective function is due to suppression of mitochondrial apoptosis signaling and induction of neuroprotective genes, including Bcl-2 and neurotrophic factors. Rasagiline inhibits the mitochondrial membrane permeabilization, an initial stage in apoptosis, but the mechanism has been elusive. In this paper, it was investigated how rasagiline regulates mitochondrial death cascade in apoptosis induced in SH-SY5Y cells by PK11195, a ligand of the outer membrane translocator protein of 18 kDa. Rasagiline prevented release of cytochrome c (Cyt-c), and the following caspase 3 activation, ATP depletion and apoptosis, but did not inhibit the mitochondrial membrane potential collapse, in contrast to Bcl-2 overexpression. Rasagiline stabilized the mitochondrial contact site and suppressed Cyt-c release into cytoplasm, which should be the critical point for the regulation of apoptosis. Monoamine oxidase was not associated with anti-apoptotic activity of rasagiline in PK11195-induced apoptosis.

In Parkinson's disease, cell death of dopamine neurons in the substantia nigra progresses and neuroprotective therapy is required to halt neuronal loss. In cellular and animal models, selegiline [(-)deprenyl] and rasagiline, inhibitors of type B monoamine oxidase (MAO)-B, protect neuronal cells from programmed cell death. In this paper, the authors review their recent results on the molecular mechanisms by which MAO inhibitors prevent the cell death through the induction of antiapoptotic, prosurvival genes. MAO-A mediates the induction of antiapoptotic bcl-2 and mao-a itself by rasagiline, whereas a different mechanism is associated with selegiline. Rasagiline and selegiline preferentially increase GDNF and BDNF in nonhuman primates and Parkinsonian patients, respectively. Enhanced neurotrophic factors might be applicable to monitor the neurorescuing activity of neuroprotection.

Neuroprotection has been proposed in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, to delay or halt disease progression or reverse neuronal deterioration. The inhibitors of type B monoamine oxidase (MAO), rasagiline and (-)deprenyl, prevent neuronal loss in cellular and animal models of neurodegenerative disorders by intervening in the death signal pathway in mitochondria. In addition, rasagiline and (-)deprenyl increase the expression of anti-apoptotic Bcl-2 protein family and neurotrophic factors. Neurotrophic factors, especially glial cell line-derived neurotrophic factor (GDNF) and brain-derived derived neurotrophic factor (BDNF), are required not only for growth and maintenance of developing neurons, but also for function and plasticity of distinct population of adult neurons. GDNF and BDNF have been reported to reduce Parkinson and Alzheimer's diseases, respectively. GDNF protects the nigra-striatal dopamine neurons in animal models of Parkinson's disease, and its administration has been tried as a disease-modifying therapy for parkinsonian patients. However, the results of clinical trials have not been fully conclusive and more practical ways to enhance GDNF levels in the targeted neurons are essentially required for future clinical application. Rasagiline and (-)deprenyl induced preferentially GDNF and BDNF in cellular and non-human primate experiments, and (-)deprenyl increased BDNF level in the cerebrospinal fluid of parkinsonian patients. In this paper, we review the induction of GDNF and BDNF by these MAO inhibitors as a strategy of neuroprotective therapy. The induction of prosurvival genes is discussed in relation to a possible disease-modifying therapy with MAO inhibitors in neurodegenerative disorders.

In Parkinson's disease, type B monoamine oxidase (MAO-B) is proposed to play an important role in the pathogenesis through production of reactive oxygen species and neurotoxins from protoxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In addition, inhibitors of MAO-B protect neurons in the cellular and animal models of Parkinson's and Alzheimer's diseases. However, the role of type A MAO (MAO-A) in neuronal death and neuroprotection by MAO-B inhibitors has been scarcely elucidated. This chapter presents our recent results on the involvement of MAO-A in the activation of mitochondrial death signal pathway and in the induction of prosurvival genes to prevent cell death with MAO-B inhibitors. The roles of MAO-A in the regulation of neuronal survival and death are discussed in concern to find a novel strategy to protect neurons in age-associated neurodegenerative disorders and depression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Neuroprotective therapy has been proposed for age-related neurodegenerative disorders, including Parkinson's disease. Inhibitors of type B monoamine oxidase (MAOB-Is), rasagiline and (-)deprenyl, are the most promising candidate neuroprotective drugs. Clinical trials of rasagiline in patients with Parkinson's disease suggest that rasagiline may have some disease-modifying effects. Results using animal and cellular models have proved that the MAOB-Is protect neurons by the intervention of 'intrinsic' mitochondrial apoptotic cascade and the induction of prosurvival antiapoptotic Bcl-2 and neurotrophic factors. Rasagiline-related MAOB-Is prevent mitochondrial permeability transition induced by various insults and activation of subsequent apoptotic cascades: cytochrome c release, casapase activation, and condensation and fragmentation of nuclear DNA. MAOB-Is increase transcription of prosurvival genes through activating the nuclear transcription factor-(NF) system. Rasagiline increases the protein and mRNA levels of GDNF in dopaminergic SH-SY5Y cells, whereas (-)deprenyl increases those of BDNF. Systemic administration of (-)deprenyl and rasagiline increases these neurotrophic factors in the cerebrospinal fluid from patients with Parkinson's disease and nonhuman primates. This review presents recent advances in our understanding of the neuroprotection offered by MAOB-Is and possible evaluation of neuroprotective efficacy in clinical samples is discussed.

Mitochondrial monoamine oxidase (MAO) has been considered to be involved in neuronal degeneration either by increased oxidative stress or protection with the inhibitors of type B MAO (MAO-B). In this paper, the role of type A MAO (MAO-A) in apoptosis was studied using human neuroblastoma SH-SY5Y cells, where only MAO-A is expressed. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, an MAO-A inhibitor, reduced membrane potential, DeltaPsim, in isolated mitochondria, and induced apoptosis in the cells, which 5-hydroxytryptamine, an MAO-A substrate, prevented. In contrast, beta-phenylethylamine, an MAO-B substrate, did not suppress the DeltaPsim decline by N-methyl(R)salsolinol. The binding of N-methyl(R)salsolinol to mitochondria was inhibited by clorgyline, a MOA-A inhibitor, but not by (-)deprenyl, an MAO-B inhibitor. RNA interference targeting MAO-A significantly reduced the binding of N-methyl(R)salsolinol with simultaneous reduction in the MAO activity. To examine the intervention of MAO-B in the apoptotic process, human MAO-B was transfected to SH-SY5Y cells, but the sensitivity to N-methyl(R)salsolinol was not affected, even although the activity and protein of MAO increased markedly. These results demonstrate a novel function of MAO-A in the binding of neurotoxins and the induction of apoptosis, which may account for neuronal cell death in neurodegenerative disorders, including Parkinson's disease.

Six main sesquiterpene lactones (germacranolides) from Calea urticifolia were evaluated for in vitro cytotoxicity against human tumor cell lines HL60 and SW480 cells. Among them, arucanolide and parthenolide displayed marked cytotoxicity against both cell lines. Arucanolide exhibited a low IC(50) in HL60 cells. The cytotoxic activity of arucanolide was observed at lower concentrations compared to that of parthenolide, which has been reported to be a typical and simple germacranolide. The activity was found to be mainly due to apoptosis that was assessed by morphological findings, DNA ladder formation (24 - 36 h), and flow cytometric analysis in HL60 cells. Western blotting and an apoptosis inhibition assay using caspase inhibitors did not demonstrate the activation of any caspases tested. However, the mitochondrial membrane potential of HL60 cells was lost after 24-h treatment with arucanolide, and concurrently apoptosis-inducing factor (AIF) released from mitochondria was detected by Western blot analysis. The inactivation of nuclear factor-kappaB, which has been commonly shown in parthenolide-induced apoptosis, did not occur in arucanolide-induced apoptosis. Taken together, the findings presented here indicate that arucanolide induced marked apoptosis in HL60 cells mainly by dissipating mitochondrial membrane potential, which would trigger AIF-induced apoptosis.

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, DeltaPsim, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of DeltaPsim. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced DeltaPsim, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the DeltaPsim reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Sal-induced loss of DeltaPsim and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.