chiniofon and Alzheimer-Disease

The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated.

Topics: Aging; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Hydroxyquinolines; Iron; Iron Chelating Agents; Mice; Mice, Inbred C57BL; Mice, Transgenic; Parkinson Disease

Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer's disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Anxiety Agents; Gabapentin; Humans; Hydroxyquinolines; Small Molecule Libraries

In many of the neurodegenerative diseases, such as Alzheimer's disease (AD) and AD-related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected-brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid β (Aβ) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of Aβ. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron-responsive elements (IRE) RNA stem loops in the 5' untranslated region (5'UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron-chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter-related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Humans; Hydroxyquinolines; Iron Chelating Agents; Neuroprotective Agents

Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Cycle Checkpoints; Chelating Agents; Cholinesterase Inhibitors; Humans; Hydroxyquinolines; Indans; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Oligopeptides; Piperazines

In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Chelating Agents; Homeostasis; Humans; Hydroxyquinolines; Ions; Metals; Neurodegenerative Diseases

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cell Cycle; Cell Survival; Drug Design; Enzyme Activation; Humans; Hydroxyquinolines; Indans; Iron Chelating Agents; MAP Kinase Signaling System; Nerve Growth Factors; Neurons; Neuroprotective Agents; Protein Kinase C

Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer's disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Catechin; Cell Cycle; Humans; Hydroxyquinolines; Iron; Iron Chelating Agents; Neurodegenerative Diseases; Neuroprotective Agents; PC12 Cells; Piperazines; Rats

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UT

Topics: Alzheimer Disease; Animals; Antiparkinson Agents; Humans; Hydroxyquinolines; Indans; Models, Biological; Neuroprotective Agents; Parkinson Disease; Selegiline

Fibrillation of amyloid beta (Aβ) is the key event in the amyloid neurotoxicity process that induces a chain of toxic events including oxidative stress, caspase activation, poly(ADP-ribose) polymerase cleavage, and mitochondrial dysfunction resulting in neuronal loss and memory decline manifesting as clinical dementia in humans. Herein, we report the development of a novel, biologically active supramolecular probe, INHQ, and achieve functional nanoarchitectures via a self-assembly process such that ultralong fibers are achieved spontaneously. With specifically decorated functional groups on INHQ such as imidazole, hydroxyquinoline, hydrophobic chain, and hydroxyquinoline molecules, these ultralong fibers coassembled efficiently with toxic Aβ oligomers and mitigated the amyloid-induced neurotoxicity by blocking the aforementioned biochemical events leading to neuronal damage in mice. These functional ultralong "Artificial Fibers" morphologically resemble the amyloid fibers and provide a higher surface area of interaction that improves its clearance ability against the Aβ aggregates. The efficacy of this novel INHQ molecule was ascertained by its high ability to interact with Aβ. Moreover, this injectable, ultralong INHQ functional "artificial fiber" translocates through the blood-brain barrier and successfully attenuates the amyloid-triggered neuronal damage and pyknosis in the cerebral cortex of wild-type mouse. Utilizing various spectroscopic techniques, morphology analysis, and in vitro, in silico, and in vivo studies, these ultralong INHQ fibers are proven to hold great promise for treating neurological disorders at all stages with a potential to replace the existing medications, reduce complications in the brain, and eradicate the amyloid-triggered neurotoxicity implicated in numerous disorders in human through a rare synergistic mechanism.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Brain; Humans; Hydroxyquinolines; Mice; Neurons

A series of novel 4-

Topics: Acetylcholinesterase; Alzheimer Disease; Amines; Aminoquinolines; Benzothiazoles; Carbon; Cholinesterase Inhibitors; Galantamine; Humans; Hydroxyquinolines; Kinetics; Molecular Docking Simulation; Morpholines; Structure-Activity Relationship; Sulfonic Acids

Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD).. To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD.. Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid β (Aβ) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aβ species, and the effects of compound 2 on apoptotic cascade.. Compounds 2-4 competitively inhibited cathepsin B β-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aβ aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 μM. Compound 2 exerted neuroprotective effects towards Aβ toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aβ1-42.. Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Apoptosis; Blood-Brain Barrier; Capillary Permeability; Cell Line, Tumor; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Humans; Hydroxyquinolines; Ligands; Neuroprotective Agents; Protein Aggregation, Pathological

Inhibitory modulation toward de novo protein aggregation is likely to be a vital and promising therapeutic strategy for understanding the molecular etiology of amyloid related diseases such as Alzheimer's disease (AD). The building up of toxic oligomeric and fibrillar amyloid aggregates in the brain plays host to a downstream of events, causing damage to axons, dendrites, synapses, signaling, transmission, and finally cell death. Herein, we introduce a novel conjugated polymer (CP), hydroxyquinoline appended polyfluorene (PF-HQ), which has a typical "amyloid like" surface motif and exhibits inhibitory modulation effect on amyloid β (Aβ) aggregation. We delineate inhibitory effects of PF-HQ based on Thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism (CD), and Fourier transform infrared (FTIR) studies. The amyloid-like PF-HQ forms nano coaggregates by templating with toxic amyloid intermediates and displays improved inhibitory impacts toward Aβ fibrillation and diminishes amyloid cytotoxicity. We have developed a CP based modulation strategy for the first time, which demonstrates beneficiary amyloid-like surface motif to interact efficiently with the protein, the pendant side groups to trap the toxic amyloid intermediates as well as optical signal to acquire the mechanistic insight.

Topics: Alzheimer Disease; Amino Acid Motifs; Amyloid; Fluorenes; Hydroxyquinolines; Peptide Fragments; Protein Aggregation, Pathological; Protein Binding

A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer's disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1-42 aggregation, rapid H2O2 scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2 within 200-220min and possesses GPx-like activity (v0=106.0μM·min(-1)), enabling modulation of metal-induced Aβ aggregation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Copper; Drug Design; Humans; Hydroxyquinolines; Membranes, Artificial; Peptide Fragments; Protein Aggregates

Low intracerebroventricular (icv) doses of streptozotocin (STZ) produce regionally specific brain neurochemical changes in rats that are similar to those found in the brain of patients with sporadic Alzheimer's disease (sAD). Since oxidative stress is thought to be one of the major pathologic processes in sAD, catalase (CAT) activity was estimated in the regional brain tissue of animals treated intracerebroventricularly with STZ and the multitarget iron chelator, antioxidant and MAO-inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline]. Five-day oral pre-treatment of adult male Wistar rats with 10 mg/kg/day M30 dose was followed by a single injection of STZ (1 mg/kg, icv). CAT activity was measured colorimetrically in the hippocampus (HPC), brain stem (BS) and cerebellum (CB) of the control, STZ-, M30- and STZ + M30-treated rats, respectively, 4 weeks after the STZ treatment. STZ-treated rats demonstrated significantly lower CAT activity in all three brain regions in comparison to the controls (p < 0.05 for BS and CB, p < 0.01 for HPC). M30 pre-treatment of the control rats did not influence the CAT activity in HPC and CB, but significantly increased it in BS (p < 0.05). M30 pre-treatment of STZ-treated rats significantly increased CAT activity in the HPC in comparison to the STZ treatment alone (p < 0.05) and normalized to the control values. These findings are in line with the assumption that reactive oxygen species contribute to the pathogenesis of STZ in a rat model of sAD and indicate that multifunctional iron chelators such as M30 might also have beneficial effects in this non-transgenic sAD model.

Topics: Alzheimer Disease; Animals; Antioxidants; Brain; Catalase; Colorimetry; Disease Models, Animal; Hydroxyquinolines; Iron Chelating Agents; Male; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Rats, Wistar; Streptozocin

The extracellular accumulation of amyloid β (Aβ) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Aβ:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1-10 μm and suppress the formation of large (>30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzothiazoles; Biophysics; Caenorhabditis elegans; Cells, Cultured; Cerebral Cortex; Chromatography, Gel; Clioquinol; Enzyme-Linked Immunosorbent Assay; Humans; Hydroxyquinolines; Mice; Microscopy, Electron; Neurons; Peptide Fragments; Protein Binding; Scattering, Small Angle; Thiazoles

Novel effective treatment is urgently needed for sporadic Alzheimer's disease (sAD). M30 ([5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline]) and HLA-20 (5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline) are brain permeable, iron chelating compounds with antioxidant activity, showing also neuroprotective activity in animal models of neurodegeneration.Weaimed to explore their therapeutic potential in non-transgenic (non-Tg) rat model of sAD developed by intracerebroventricular administration of streptozotocin (STZ-icv).. Therapeutic effects of chronic oral M30 (2 and 10 mg/kg) and HLA20 (5 and 10 mg/kg) treatment on cognitive impairment in STZ-icv rat model were explored by Morris Water Maze (MWM) and Passive Avoidance (PA) tests in neuropreventive and neurorescue paradigms. Data were analysed by Kruskal–Wallis and Mann–Whitney U test (p b 0.05).. Five-day oral pre-treatment with M30 and HLA20 dose-dependently prevented development of spatial memory impairment (MWM probe trial-time +116%/M30; +60%/HLA20) in STZ-icv rat model (p b 0.05). Eleven-week oral treatment with M30 (3×/week), initiated 8 days after STZ-icv administration dosedependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after the STZ-icv treatment — 59%; p b 0.05) and fully restored them in PA test (+314%; p b 0.05). Chronic M30 treatment fully restored (−47%/PHF1;−65%/AT8; p b 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased expression of insulin degrading enzyme (+37%; p b 0.05) in hippocampus.. The results provide first evidence of therapeutic potential of M30 and HLA20 in STZ-icv rat model of sAD with underlying molecular mechanism, further supporting the important role of multi-target ironchelators in sAD treatment.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Hydroxyquinolines; Iron Chelating Agents; Male; Memory Disorders; Memory, Long-Term; Neuroprotective Agents; Piperazines; Rats, Wistar; Streptozocin

Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a pathogenic factor in neurodegeneration because it could be responsible for damage involving oxidative stress and protein aggregation. As such, metal ions represent an effective target. To improve the metal-binding ability of cyclodextrin, we synthesized three new 8-hydroxyquinoline-cyclodextrin conjugates with difunctionalized cyclodextrins. In particular, the 3-difunctionalized regioisomer represents the first example of cyclodextrin with two pendants at the secondary rim, resulting in a promising compound. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self-induced amyloid-β aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxyquinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal-induced protein aggregation. Therefore, these compounds could have potential as therapeutic agents in diseases related to protein aggregation and metal dyshomeostasis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Chelating Agents; Coordination Complexes; Cyclodextrins; Hydroxyquinolines; Metals; Neurodegenerative Diseases; Oxidative Stress; Protein Aggregation, Pathological; Zinc

Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Brain; Cognition; Disease Models, Animal; Female; Hydroxyquinolines; Lipid Peroxidation; Male; Microglia; Neuroprotective Agents; Nootropic Agents; Rats, Transgenic; Recognition, Psychology

Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using (77)Se, (1)H and (13)C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aβ. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aβ aggregation, and an ability to disassemble preformed self- and metal-induced Aβ aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg(-1). Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Azoles; Biocompatible Materials; Blood-Brain Barrier; Catalysis; Chelating Agents; Clioquinol; Glutathione Peroxidase; Hydroxyquinolines; Isoindoles; Magnetic Resonance Spectroscopy; Metals; Mice; Organoselenium Compounds; Selenium

Increasing evidence suggests that dysregulation of brain insulin/insulin receptor (InsR) and insulin signaling cascade are associated with the pathogenesis of Alzheimer's disease (AD). Our group has designed and synthesized a series of multi-target iron chelating, brain permeable compounds for AD. One leading multi-target compound, M30 possesses the neuroprotective N-propargyl moiety of the anti-Parkinsonian, monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect®) and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Positive outcomes for the behavioral/cognitive and neuroprotective effects of M30 were recently obtained in preclinical experimental studies, regarding pathological aspects relevant to ageing and AD. We report that chronic treatment with M30 (1 and 5 mg/kg p.o; three times a week for 9 months) significantly elevated cortical insulin and InsR transcript and protein expression, respectively and increased the phosphorylated form of glycogen synthase kinase-3β in the frontal cortex of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice. In addition, M30 treatment upregulated the levels of hypoxia-inducible factor (HIF)-1α and expression of its target genes involved in glycolysis including, aldolase A, enolase-1 and glucose transporter-1 (Glut-1), in the frontal cortex of APP/PS1 mice. Treatment with M30 also lead to an increase in the hepatic protein expression levels of InsR and Glut-1 and lowered the increase in blood glucose levels following glucose tolerance test. The present findings indicate that the multifunctional iron chelating drug, M30 regulates major brain glucose metabolism parameters and thus, might be beneficial for AD, in which impaired neuronal insulin signaling and Glut expression have been implicated.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Drug Delivery Systems; Frontal Lobe; Glucose Transporter Type 1; Glycolysis; Hydroxyquinolines; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Iron Chelating Agents; Male; Mice; Presenilin-1; Signal Transduction

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Hep G2 Cells; Humans; Hydroxyquinolines; Indans; Male; Memory; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Piperidines; Propylamines; Rats

The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multi-target nontoxic, lipophilic, brain permeable monoamine oxidase inhibitor and iron chelating-radical scavenging drug, M30, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) Alzheimer's disease (AD) mice.. Here, we report that systemic treatment of APP/PS1 Tg mice with M30 for 9 months, significantly attenuated cognitive impairments in a variety of tasks of spatial learning and memory retention, working memory, learning abilities, anxiety levels, and memory for novel food and nesting behavior. Furthermore, we found that M30 reduced cerebral iron accumulation accompanied by a marked decrease in several AD-like phenotypes, including cerebral APP levels, amyloid β (Aβ) levels and plaques, phospho-APP and phospho-tau. Signaling studies revealed that M30 markedly downregulated the levels of phosphorylated cyclin-dependent kinase 5 and increased protein kinase B and glycogen synthase kinase 3β phosphorylation.. Accumulation and deposition of brain iron is central to various neuropathological processes in AD, including oxidative stress, amyloid deposition, and tau phosphorylation. Thus, the concept of iron chelation holds considerable promise as a therapeutic strategy for AD pathogenesis. Here, for the first time, we demonstrated that, when systemically administered to APP/PS1 Tg mice, our novel multifunctional iron chelating/radical scavenging compound, M30, effectively reduced Aβ accumulation and tau phosphorylation, and attenuated memory deficits.. These findings suggest that M30 is a potential therapeutic agent for the prevention and treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Behavior, Animal; Blotting, Western; Cyclin-Dependent Kinase 5; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hydroxyquinolines; Immunohistochemistry; Male; Maze Learning; Mice; Mice, Transgenic; Phosphorylation; Presenilin-1; Real-Time Polymerase Chain Reaction

Several studies have implicated the enzyme acetylcholinesterase (AChE) as well as several biometals in the pathogenesis of Alzheimer's disease (AD). A multifunctional molecule, the hybrid tacrine-8-hydroxyquinoline (named IQM-622), displays cholinergic, antioxidant, copper-complexing and neuroprotective properties. Using in vitro and in vivo models, we investigated the modulating effects of IQM-622 on amyloid β-protein (Aβ)-induced pathology as well as on chemically induced neurodegeneration by domoic acid. In the first experimental model, we observed a significant decrease in brain Aβ deposits in IQM-622-treated APP/Ps1 mice for four weeks. Moreover, IQM-622 promoted the degradation of intracellular Aβ in astrocytes, and protected against Aβ toxicity in cultured astrocytes and neurons. These findings suggest that the neuroprotective effect of IQM-622 is not only related to AChE inhibition, but also involves other mechanisms, including the modulation of Aβ-degradation pathways in AD brain. In this study we also compare the neuronal loss in CA1 hippocampal field of AD patients and of mice treated with domoic acid, giving similar patterns. Thus, we used a second experimental model by killing hippocampal neurons by domoic acid damage, in which IQM-622 increased survival in the CA1 and dentate gyrus regions of the hippocampus. Our observations suggest that administration of IQM-622 may have significant beneficial effects in neurodegenerative diseases, including AD, which course with acute or progressive neuronal death.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Cell Death; Cells, Cultured; Hippocampus; Humans; Hydroxyquinolines; Immunohistochemistry; Mice; Mice, Transgenic; Neurons; Neuroprotective Agents; Presenilin-1; Tacrine

Based on a multimodal drug design strategy for age-related neurodegenerative diseases, we have synthesized a multifunctional nontoxic, brain-permeable iron-chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of the 8-hydroxyquinoline derivative of the iron chelator, VK28. In the present short overview, we describe the neuroprotective and the neurorestorative activity of M30, acting against multiple brain targets, including regulation on amyloid β, neurogenesis, and activation of hypoxia inducible factor signaling pathways. The diverse pharmacological properties and several pathological targets of M30 make this drug potential valuable for therapeutic strategy of Alzheimer's-like neuropathology and aging.

Topics: Aging; Alzheimer Disease; Amyloidosis; Animals; Brain; Cognition Disorders; Hydroxyquinolines; Mice; Neuroprotective Agents

We report here a thorough physico-chemical study of the coordination properties of clioquinol, an oxine-type active neurological drug in Alzheimer's disease, toward biologically relevant divalent metal ions (Cu, Zn, Ni, Co and Mn). Using a fruitful combination of electrospray mass spectrometry, absorption spectrophotometry and potentiometry, we have characterized the mono- and bis-chelated metal ion species. The determination of the stability constants showed a classical thermodynamic behavior along the studied series with the cupric complexes being by far the most stable species. Our data are discussed within the scope of Alzheimer's disease.

Topics: Alzheimer Disease; Cations, Divalent; Chelating Agents; Clioquinol; Colorimetry; Drug Stability; Humans; Hydrogen-Ion Concentration; Hydroxyquinolines; Ligands; Metals; Potentiometry; Spectrophotometry; Thermodynamics

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimer's amyloid precursor protein and its toxic amyloidogenic derivative, Abeta. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1alpha signaling pathway, thus promoting HIF-1alpha mRNA and protein expression levels, as well as increasing transcription of HIF-1alpha-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 also increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimer's disease (AD), western blotting analysis of glycogen synthase kinase- 3beta (GSK-3beta) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3beta (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Abeta(25-35) toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinson's disease and AD in which oxidative stress and iron-mediated toxicity are involved.

Topics: Alzheimer Disease; Animals; Cells, Cultured; Cerebral Cortex; Chelating Agents; Drug Delivery Systems; Hydroxyquinolines; Hypoxia-Inducible Factor 1, alpha Subunit; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Up-Regulation

Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cell Line, Tumor; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Copper; Humans; Hydroxyquinolines; Magnetic Resonance Spectroscopy; Neuroprotective Agents; Propidium; Spectrometry, Mass, Electrospray Ionization; Tacrine

A novel strategy to develop site-activated multifunctional chelators for targeting multiple etiologies of Alzheimer's disease is reported. The novel prochelator HLA20A with improved cytotoxicity shows little affinity for metal ions until it is activated by binding and inhibiting acetylcholinesterase (AChE), releasing an active chelator HLA20 that modulates amyloid precursor protein (APP) regulation and beta-amyloid (Abeta) reduction, suppresses oxidative stress, and passivates excess metal ions (Fe, Cu, and Zn) in the brain.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Brain; Cell Line, Tumor; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Humans; Hydroxyquinolines; Metals; Neuroprotective Agents; Piperazines; Prodrugs; Rats

As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Behavior, Animal; Cell Line, Tumor; Clioquinol; Cognition; Copper; Disease Models, Animal; Hippocampus; Humans; Hydroxyquinolines; In Vitro Techniques; Long-Term Potentiation; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Peptide Fragments; Presenilin-1; Zinc