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)

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.
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PMID:Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. 1220 96

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326 and TV3279 [(N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl methyl carbamate], respectively were derived from rasagiline, for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and B, while its S-isomer, TV3279, lacks MAO-inhibitory activity. The actions of these drugs in the regulation of the amyloid precursor protein (APP) processing using rat PC12 and human SH-SY5Y neuroblastoma cells were examined. Both isomers stimulated the release of the non-amyloidogenic alpha-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 micro M) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via alpha-secretase activity. Using several signal transduction inhibitors, the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279 was identified. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism, whereby these ChE inhibitors regulate the secretary processes of APP via activation of the MAP kinase pathway.
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PMID:Amyloid processing and signal transduction properties of antiparkinson-antialzheimer neuroprotective drugs rasagiline and TV3326. 1285 32

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 bifunctional drug ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate]. Ladostigil combines the neuroprotective effects of the antiparkinson drug rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Here, we assessed the dual effects of lodostigil in terms of the molecular mechanism of neuroprotection and amyloid precursor protein (APP) regulation/processing by using an apoptotic model of neuroblastoma SK-N-SH cells. Ladostigil dose-dependently decreased cell death via inhibition of the cleavage and prevention of caspase-3 activation (IC50=1.05 microM) through a mechanism related to regulation of the Bcl-2 family proteins, which resulted in reduced levels of Bad and Bax and induced levels of Bcl-2 gene and protein expression. We have also followed APP regulation/processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP protein without altering APP mRNA levels, suggesting a posttranscriptional mechanism. In addition, the drug-elevated phosphorylated protein kinase C (pPKC) levels and stimulated the release of the nonamyloidogenic alpha-secretase proteolytic pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor but lacks MAO inhibitory activity, exerted neuroprotective properties and regulated APP processing, indicating that these effects are independent of MAO inhibition.
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PMID:A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing. 1693 43

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 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 drug, ladostigil (TV3326) ((N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase -A and -B and cholinesterase inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Preclinical studies show that ladostigil has antidepressant and anti-AD activities and the clinical development is planned for these dementias. In this review, we discuss the multimodal effects of ladostigil in terms of neuroprotective molecular mechanism in vivo and in vitro, which include the amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase pathways; regulation of the Bcl-2 family members; inhibition of cell death markers and up-regulation of neurotrophic factors. Altogether, these scientific findings make ladostigil a potentially valuable drug for the treatment of AD.
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PMID:The neuroprotective mechanism of action of the multimodal drug ladostigil. 1850 75

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

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

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer's and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug.
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PMID:Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. 2228 Mar 45