Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-Parkinson, selective irreversible monoamine oxidase B inhibitor drug, rasagiline (Azilect), recently approved by the US Food and Drug Administration, has been shown to possess neuroprotective-neurorescue activities in in vitro and in vivo models. Recent preliminary studies indicated the potential neuroprotective effect of the major metabolite of rasagiline, 1-(R)-aminoindan. In the current study, the neuroprotective properties of 1-(R)-aminoindan were assessed employing a cytotoxic model of human neuroblastoma SK-N-SH cells in high-density culture-induced neuronal death. We show that aminoindan (0.1-1 mumol/L) significantly reduced the apoptosis-associated phosphorylated protein, H2A.X (Ser139), decreased the cleavage of caspase 9 and caspase 3, while increasing the anti-apoptotic proteins, Bcl-2 and Bcl-xl. Protein kinase C (PKC) inhibitor, GF109203X, prevented the neuroprotection, indicating the involvement of PKC in aminoindan-induced cell survival. Aminoindan markedly elevated pPKC(pan) and specifically that of the pro-survival PKC isoform, PKCepsilon. Additionally, hydroxyaminoindan, a metabolite of a novel bifunctional drug, ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], combining cholinesterase and monoamine oxidase inhibitor activity, exerted similar neuroprotective properties. Aminoindan and hydroxyaminoindan also protected rat pheochromacytoma PC-12 cells against the neurotoxin, 6-hydroxydopamine. Our findings suggest that both metabolites may contribute to the overall neuroprotective activity of their respective parent compounds, further implicating rasagiline and ladostigil as potentially valuable drugs for treatment of a wide variety of neurodegenerative disorders of aging.
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PMID:Aminoindan and hydroxyaminoindan, metabolites of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro. 1763 68

The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent.
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PMID:Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway. 1770 52

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuroprotective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer's disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagiline-containing hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer's disease.
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PMID:Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs. 1911 Feb 7

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple central nervous system targets. We have recently synthesized multifunctional, nontoxic, brain-permeable iron-chelating drugs, M30 and HLA20, possessing the N-propargylamine neuroprotective moiety of rasagiline (Azilect) and the iron-chelating moiety of VK28. The present study demonstrates that M30 and HLA20 possess a wide range of pharmacological activities in mouse NSC-34 motor neuron cells, including neuroprotective effects against hydrogen peroxide- and 3-morpholinosydnonimine-induced neurotoxicity, induction of differentiation, and up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes (enolase1 and vascular endothelial growth factor). Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by PD98059 and GF109203X, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. A major finding was the ability of M30 to significantly extend the survival of G93A-SOD1 amyotrophic lateral sclerosis mice and delay the onset of the disease. These properties of the novel multimodal iron-chelating drugs possessing neuroprotective/neuritogenic activities may offer future therapeutic possibilities for motor neurodegenerative diseases.
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PMID:Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. 1963 99

Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administration-approved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-epsilon and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 microM, 24 h) prevented doxorubicin (0.5 microM, 24 h)-induced elevation of diastolic [Ca(2+)](i), the slowing of [Ca(2+)](i) relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase, Na(+)/Ca(2+) exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/dt(max)) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.
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PMID:TVP1022 protects neonatal rat ventricular myocytes against doxorubicin-induced functional derangements. 1991 70

The anti-Parkinsonian, irreversible, selective monoamine oxidase (MAO)-B inhibitors, selegiline (deprenyl, (R)-N-methyl-N-(1-phenylpropan-2-yl) prop-2-yn-1-amine) and rasagiline (Azilect, N-propargyl-1(R)-aminoindan), have been proven to possess neuroprotective/neurorestorative activities in cell cultures and animal models of neurodegenerative diseases. Structure-activity studies provide evidence that neuroprotection is associated with some intrinsic pharmacological action of the propargylamine moiety in these drugs. This indication and recent therapeutic approaches, entailing new drug candidates possessing diverse pharmacological properties and acting on multiple targets, have stimulated the development of two multifunctional chimeric propargylamine-derivatives: 1) ladostigil (TV3326, [(N-propargyl-(3R) 1-(R)-aminoindan-5yl)-ethyl methyl carbamate)], which combines the pharmacophore of rasagiline, with the carbamate moiety of the cholinesterase inhibitor rivastigmine, as a potential treatment for Alzheimer's disease and Lewy body disease; and 2) M30 5-[(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], where the propargylamine moiety of rasagiline was embedded onto the backbone of the neuroprotective and brain permeable iron chelator 8-hydroxyquinoline-derivative, VK28 as a potential treatment for various neurodegenerative disorders. Both multifunctional propargylamine-derivatives were found to possess neuroprotective and anti-apoptotic properties. An additional and new neuroprotective effect, shared by the propargylamine-derivative compounds, is related to their ability to regulate the processing of amyloid-beta protein precursor (AbetaPP) by the non-amyloidogenic alpha-secretase pathway. This effect was shown to involve activation of p42/44 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathway. This review will summarize and discuss current research, focused on the effect of propargylamine-related derivatives on the proteolytic processing of AbetaPP and signal transduction mechanisms.
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PMID:Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation. 2055 37