harmine and Alzheimer-Disease

Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding of how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases.

Topics: Alternative Splicing; Alzheimer Disease; Apoptosis; Benzothiazoles; Cell Cycle; Cell Differentiation; Down Syndrome; Dyrk Kinases; Enzyme Activation; Gene Dosage; Harmine; Humans; Indoles; Neoplasms; Neurodegenerative Diseases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyridazines; Receptors, Notch; Signal Transduction

In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Drug Design; Harmine; Humans; Kinetics; Neuroprotective Agents; Structure-Activity Relationship

The natural product harmine, a representative β-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Antineoplastic Agents; Apoptosis; Carbolines; Cell Line, Tumor; Cell Proliferation; Cholinesterase Inhibitors; Drug Design; Glycogen Synthase Kinase 3 beta; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship

Topics: Alzheimer Disease; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Dyrk Kinases; Glycogen Synthase Kinase 3 beta; Harmine; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Structure-Activity Relationship

β-Carboline alkaloid harmine (HAR) and harmaline (HAL) are monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors. However, whether HAR and HAL inhibit MAO or AChE selectively and competitively is unclear.. The purpose of this study was to investigate the potential competition inhibition of HAR and HAL on MAO and AChE in brain endothelial cells (RBE4) and in healthy rats to provide a basis for the application of the inhibitors in the treatment of patients with depression and with Parkinson's disease or Alzheimer's disease.. The transport properties of HAR and HAL by using blood-brain barrier models constructed with RBE4 were systematically investigated. Then, the modulation effects of HAR and HAL on CNS neurotransmitters (NTs) in healthy rat brains were determined by a microdialysis method coupled with LC-MS/MS. The competition inhibition of HAR and HAL on MAO and AChE was evaluated through real time-PCR, Western blot analysis, and molecular docking experiments.. Results showed that HAL and HAR can be detected in the blood and striatum 300 min after intravenous injection (1 mg/kg). Choline (Ch), gamma-aminobutyric acid (GABA), glutamate (Glu), and phenylalanine (Phe) levels in the striatum decreased in a time-dependent manner after the HAL treatment, with average velocities of 1.41, 0.73, 3.86, and 1.10 (ng/ml)/min, respectively. The Ch and GABA levels in the striatum decreased after the HAR treatment, with average velocities of 1.16 and 0.22 ng/ml/min, respectively. The results of the cocktail experiment using the human liver enzyme indicated that the IC. NT analysis results showed that HAL and HAR selectively affect AChE in vivo. HAL and HAR may be highly and suitably developed for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Animals; Brain; Carbolines; Cholinesterase Inhibitors; Chromatography, Liquid; Endothelial Cells; Harmaline; Harmine; Humans; Male; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rats; Tandem Mass Spectrometry

Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity.

Topics: Alzheimer Disease; Doxorubicin; Drug Evaluation, Preclinical; Drug Synergism; Dyrk Kinases; Harmine; Humans; MCF-7 Cells; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; tau Proteins

Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1.5-fold higher than that in healthy people, thus causing a 1.5-fold increase in Aβ production. However, when comparing the causal relationship of Aβ accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aβ production alone. In this study, we found that neprilysin, a major Aβ-degrading enzyme, was downregulated in DS patient-derived fibroblasts, compared with healthy people-derived fibroblasts. Treatment with harmine, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is located in the DS critical region of chromosome 21, and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. These results suggest that a decrease in the Aβ catabolic rate may be, at least in part, one of the causes for accelerated AD-like pathogenesis in DS patients if a similar event occurs in the brains, and that neprilysin activity may be regulated directly or indirectly by DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Brain; Cell Line; Chromosomes, Human, Pair 21; Down Syndrome; Down-Regulation; Dyrk Kinases; Enzyme Inhibitors; Fibroblasts; Harmine; Humans; Neprilysin; Phosphorylation; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Tyrosine

Starting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1. Then, our best submicromolar to nanomolar inhibitors were evaluated towards the closest members of the aforementioned kinases: DYRK1B and CLK4, as well as the subfamily CLK2-3. Several compounds appear to be particularly promising for the development of tools in the battle against Alzheimer's disease.

Topics: Alzheimer Disease; Drug Evaluation, Preclinical; Humans; KB Cells; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases

Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by (1)H NMR, (13)C NMR and HRMS. The evaluation of their anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3 ± 1.9% at 100 µM). Compound 2 exhibited the best anti-AChE activity (IC50=1.9 ± 1.5 µM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC50=5.0 ± 0.3 µM (3a) and IC50=6.3 ± 0.4 µM (3b) against HCT 116 cells, IC50=5.0 ± 1.0 µM (3d) against MCF7 cells).

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carbon-13 Magnetic Resonance Spectroscopy; Cholinesterase Inhibitors; Cycloaddition Reaction; Harmine; HCT116 Cells; Humans; Isoxazoles; Lipoxygenase Inhibitors; MCF-7 Cells; Peganum; Proton Magnetic Resonance Spectroscopy; Structure-Activity Relationship; Tamoxifen; Xanthine Oxidase

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC50 = 10.4 µM) was obtained for harmine 1 and cytotoxic activities (IC50 = 0.2 µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC50 = 29.2 and 55.5 µM, respectively).

Topics: Acetylcholinesterase; Alzheimer Disease; Anti-Inflammatory Agents; Antineoplastic Agents; Arachidonate 5-Lipoxygenase; Cell Proliferation; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Harmine; HCT116 Cells; Humans; Inflammation; Isoxazoles; Lipoxygenase Inhibitors; MCF-7 Cells; Molecular Structure; Structure-Activity Relationship

Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.

Topics: Alzheimer Disease; Blotting, Western; Carbolines; Cell Line, Tumor; Dyrk Kinases; Harmine; Humans; Phosphorylation; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; tau Proteins