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

Abstract: Our studies have provided new insights into the biological mechanism of neuroprotection of the anti‐Parkinson drug, rasagiline [N‐propargyl‐(1R)‐aminoindan], involving the association of Bcl‐2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal‐induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N‐propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCε mRNA; induction of Bcl‐XL, Bcl‐w, and brain‐derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCγ, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro‐caspase‐3 and poly(ADP‐ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum‐free‐induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC‐dependent cell survival activity of rasagiline. Structure activity studies have established that N‐propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron‐chelating property for the treatment and/or prevention of neurodegenerative diseases.

[1]  J. Connor,et al.  Iron, brain ageing and neurodegenerative disorders , 2004, Nature Reviews Neuroscience.

[2]  M. Youdim,et al.  Neuroprotection via pro‐survival protein kinase C isoforms associated with Bcl‐2 family members , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  M. Youdim,et al.  Regulation of protein kinase C by the anti‐Parkinson drug, MAO‐B inhibitor, rasagiline and its derivatives, in vivo , 2004, Journal of neurochemistry.

[4]  Y. Akao,et al.  N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor , 2004, Neurochemistry International.

[5]  M. Youdim,et al.  Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6‐Hydroxydopamine and Iron Chelators, Desferal and VK‐28 , 2004, Annals of the New York Academy of Sciences.

[6]  M. Youdim,et al.  Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats , 2004, Neuropharmacology.

[7]  M. Youdim,et al.  The importance of propargylamine moiety in the anti‐ Parkinson drug rasagiline and its derivatives for MAPK‐ dependent amyloid precursor protein processing , 2003, The FASEB Journal.

[8]  M. Youdim,et al.  The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. , 2003, Biochemical pharmacology.

[9]  M. Youdim,et al.  Attenuation of MPTP‐induced dopaminergic neurotoxicity by TV3326, a cholinesterase‐monoamine oxidase inhibitor , 2003, Journal of neurochemistry.

[10]  H. Hsu,et al.  Suppression of Protein Kinase C&agr; Triggers Apoptosis Through Down-Regulation of BCL-XL in a Rat Hepatic Epithelial Cell Line , 2003, Shock.

[11]  J. Nutt,et al.  A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. , 2002, Archives of neurology.

[12]  T. Amit,et al.  The involvement of mitogen‐activated protein (MAP) kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline , 2002 .

[13]  Y. Akao,et al.  Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan , 2002, Journal of neurochemistry.

[14]  Y. Akao,et al.  An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in human dopaminergic SH-SY5Y cells , 2002, Neuroscience Letters.

[15]  M. Youdim,et al.  Molecular Basis of Neuroprotective Activities of Rasagiline and the Anti-Alzheimer Drug TV3326 [lpar;N-Propargyl-(3R) Aminoindan-5-YL)-Ethyl Methyl Carbamate] , 2001, Cellular and Molecular Neurobiology.

[16]  M. Naoi,et al.  Future of neuroprotection in Parkinson's disease. , 2001, Parkinsonism & related disorders.

[17]  Y. Akao,et al.  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 , 2001, Journal of neurochemistry.

[18]  W Tatton,et al.  The Anti‐Parkinson Drug Rasagiline and Its Cholinesterase Inhibitor Derivatives Exert Neuroprotection Unrelated to MAO Inhibition in Cell Culture and in Vivo , 2001, Annals of the New York Academy of Sciences.

[19]  M. Naoi,et al.  Antiapoptotic Properties of Rasagiline, N‐Propargylamine‐1(R)‐aminoindan, and Its Optical (S)‐Isomer, TV1022 , 2001, Annals of the New York Academy of Sciences.

[20]  P. Maher.  How Protein Kinase C Activation Protects Nerve Cells from Oxidative Stress-Induced Cell Death , 2001, The Journal of Neuroscience.

[21]  A. Davies,et al.  Reciprocal developmental changes in the roles of Bcl-w and Bcl-x(L) in regulating sensory neuron survival. , 2001, Development.

[22]  M. Murer,et al.  Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease , 2001, Progress in Neurobiology.

[23]  Shigeomi Shimizu,et al.  Bcl‐2 family: Life‐or‐death switch , 2000, FEBS letters.

[24]  H. Ruan,et al.  p90RSK Blocks Bad-mediated Cell Death via a Protein Kinase C-dependent Pathway* , 1999, The Journal of Biological Chemistry.

[25]  E. Hirsch,et al.  Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. , 1999, Neuroreport.

[26]  E. Shohami,et al.  Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. , 1999, European journal of pharmacology.

[27]  G. Mealing,et al.  Evidence that Brain‐Derived Neurotrophic Factor Neuroprotection Is Linked to Its Ability to Reverse the NMDA‐Induced Inactivation of Protein Kinase C in Cortical Neurons , 1999, Journal of neurochemistry.

[28]  W. May,et al.  A Functional Role for Mitochondrial Protein Kinase Cα in Bcl2 Phosphorylation and Suppression of Apoptosis* , 1998, The Journal of Biological Chemistry.

[29]  T. Takeshima,et al.  Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor , 1998, Neuroreport.

[30]  Z. Szallasi,et al.  Overexpression of Protein Kinase C Isoform but not δ in Human Interleukin-3–Dependent Cells Suppresses Apoptosis and Induces bcl-2 Expression , 1998 .

[31]  R. Maroto,et al.  BCL‐2‐Related Protein Expression in Apoptosis: Oxidative Stress Versus Serum Deprivation in PC12 Cells , 1997, Journal of neurochemistry.

[32]  A. Kribben,et al.  AVP-induced activation of MAP kinase in vascular smooth muscle cells is mediated through protein kinase C. , 1993, The American journal of physiology.

[33]  L. Greene,et al.  Multiple agents rescue PC12 cells from serum-free cell death by translation- and transcription-independent mechanisms , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[34]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[35]  A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. , 2005, Archives of neurology.

[36]  M. Naoi,et al.  N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2 , 2005, Journal of Neural Transmission.

[37]  M. Naoi,et al.  Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine , 2001, Journal of Neural Transmission.

[38]  Z. Szallasi,et al.  Overexpression of protein kinase C isoform epsilon but not delta in human interleukin-3-dependent cells suppresses apoptosis and induces bcl-2 expression. , 1998, Blood.