Novel Neuroprotective Mechanism of Action of Rasagiline Is Associated with Its Propargyl Moiety: Interaction of Bcl-2 Family Members with PKC Pathway

Weinreb, Orly

doi:10.1196/annals.1344.030

Cited by 65 publications

(40 citation statements)

References 30 publications

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“…One such molecule is rasagiline, which is an established drug for the treatment of PD. Rasagiline prevents apoptosis via multiple intracellular processes including the induction of survival genes and the suppression of proapoptotic genes (483,825,869). In addition, rasagiline can mediate direct PTP inhibition, as demonstrated in cellula and in isolated mitochondria (8).…”

Section: Inhibitors Of the Permeability Transition Porementioning

confidence: 99%

Mitochondrial Membrane Permeabilization in Cell Death

Kroemer¹,

Galluzzi²,

Brenner³

2007

Physiological Reviews

3,160

2,742

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Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

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Section: Inhibitors Of the Permeability Transition Porementioning

confidence: 99%

Mitochondrial Membrane Permeabilization in Cell Death

Kroemer¹,

Galluzzi²,

Brenner³

2007

Physiological Reviews

3,160

2,742

View full text Add to dashboard Cite

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“…It also incorporates a propargyl ring within its molecular structure, and has been shown to provide protective effects for dopamine neurons in a wide variety of in vitro and in vivo model systems. 119,205,206 Rasagiline has also been shown to have antiapoptotic effects, and to act by binding to GAPDH, preserving mitochondrial membrane potential, and preventing activation of the caspase system. 207,208 Protection in model systems might also relate to the capacity of the drug to induce upregulation of trophic factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, and to activate the PI3K/AKT signaling pathway.…”

Section: Apoptosismentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

760

658

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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“…Functional categorization of the differentially expressed genes in the Cr(VI) treated cells identified the differential expression of several genes involved in apoptosis (Table 3) potentially resulting in the induction of apoptosis as a likely response of the fibroblasts to Cr(VI) exposure. Pro-apoptotic genes such as phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) [41], B-cell CLL/ lymphoma 6 (BCL6) [42], tumor protein p53 inducible nuclear protein 1 (TP53INP1) [43], tumor necrosis factor receptor superfamily, member 10 A and B (TNFRS10A and B) [44], BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) [45], death effector domain containing 2 (DEDD2) [46], etc, were overexpressed while antiapoptotic genes such as cyclin dependent kinase 9 (CDK9) [47], protein kinase C alpha (PKCA) [48], fas apoptotic inhibitory molecule (FAIM) [49], kruppellike factor 2 (KLF2) [50], etc, were repressed in the Cr(VI) exposed cells facilitating apoptosis induction. The results of TUNEL assay further confirmed the microarray findings and demonstrated the induction of apoptosis as a cellular response of the fibroblasts to Cr(VI) toxicity.…”

Section: Discussionmentioning

confidence: 99%