Publications by authors named "Francesc X Sureda"

37 Publications

Pharmacological Strategies to Improve Dendritic Spines in Alzheimer's Disease.

J Alzheimers Dis 2020 Dec 2. Epub 2020 Dec 2.

Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain.

To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.
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http://dx.doi.org/10.3233/JAD-201106DOI Listing
December 2020

Gambierdiscus and Fukuyoa as potential indicators of ciguatera risk in the Balearic Islands.

Harmful Algae 2020 Nov 22;99:101913. Epub 2020 Oct 22.

IRTA, Ctra. Poble Nou Km 5.5, 43540, Sant Carles de la Ràpita, Tarragona, Spain. Electronic address:

Gambierdiscus and Fukuyoa are genera of toxic dinoflagellates which were mainly considered as endemic to marine intertropical areas, and that are well known as producers of ciguatoxins (CTXs) and maitotoxins (MTXs). Ciguatera poisoning (CP) is a human poisoning occurring after the consumption of fish or more rarely, shellfish containing CTXs. The presence of these microalgae in a coastal area is an indication of potential risk of CP. This study assesses the risk of CP in the Balearic Islands (Western Mediterranean Sea) according to the distribution of both microalgae genera, and the presence of CTX-like and MTX-like toxicity in microalgal cultures as determined by neuro-2a cell based-assay (neuro-2a CBA). Genetic identification of forty-three cultured microalgal strains isolated from 2016 to 2019 revealed that all of them belong to the species G. australes and F. paulensis. Both species were widely distributed in Formentera, Majorca and Minorca. Additionally, all strains of G. australes and two of F. paulensis exhibited signals of CTX-like toxicity ranging respectively between 1 and 380 and 8-16 fg CTX1B equivalents (equiv.) • cell. Four extracts of F. paulensis exhibited a novel toxicity response in neuro-2a cells consisting of the recovery of the cell viability in the presence of ouabain and veratridine. In addition, G. australes showed MTX-like toxicity while F. paulensis strains did not. Overall, the low CTX-like toxicities detected indicate that the potential risk of CP in the Balearic Islands is low, although, the presence of CTX-like and MTX-like toxicity in those strains reveal the necessity to monitor these genera in the Mediterranean Sea.
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http://dx.doi.org/10.1016/j.hal.2020.101913DOI Listing
November 2020

Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment.

Int J Mol Sci 2019 Dec 30;21(1). Epub 2019 Dec 30.

Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain.

Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.
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http://dx.doi.org/10.3390/ijms21010255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981493PMC
December 2019

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

Eur J Med Chem 2019 Oct 17;180:613-626. Epub 2019 Jul 17.

Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address:

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.051DOI Listing
October 2019

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I Receptor Ligands in Female SAMP8 Mice.

Neurotherapeutics 2019 04;16(2):416-431

Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I-Imidazoline receptors (I-IR) are widely distributed in the central nervous system, and dysregulation of I-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.
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http://dx.doi.org/10.1007/s13311-018-00681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554384PMC
April 2019

Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists.

ACS Chem Neurosci 2018 11 1;9(11):2722-2730. Epub 2018 Jun 1.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB) , Universitat de Barcelona , Av. Joan XXIII, 27-31 , 08028 Barcelona , Spain.

This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
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http://dx.doi.org/10.1021/acschemneuro.8b00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249113PMC
November 2018

Towards a Novel Class of Multitarget-Directed Ligands: Dual P2X7-NMDA Receptor Antagonists.

Molecules 2018 Jan 21;23(1). Epub 2018 Jan 21.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.

Multi-target-directed ligands (MTDLs) offer new hope for the treatment of multifactorial complex diseases such as Alzheimer's Disease (AD). Herein, we present compounds aimed at targeting the NMDA and the P2X7 receptors, which embody a different approach to AD therapy. On one hand, we are seeking to delay neurodegeneration targeting the glutamatergic NMDA receptors; on the other hand, we also aim to reduce neuroinflammation, targeting P2X7 receptors. Although the NMDA receptor is a widely recognized therapeutic target in treating AD, the P2X7 receptor remains largely unexplored for this purpose; therefore, the dual inhibitor presented herein-which is open to further optimization-represents the first member of a new class of MTDLs.
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http://dx.doi.org/10.3390/molecules23010230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017257PMC
January 2018

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists.

Molecules 2016 Aug 6;21(8). Epub 2016 Aug 6.

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.
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http://dx.doi.org/10.3390/molecules21081027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272859PMC
August 2016

Molecular links between early energy metabolism alterations and Alzheimer's disease.

Front Biosci (Landmark Ed) 2016 Jan 1;21:8-19. Epub 2016 Jan 1.

Unitats de Bioquimica i, Facultat de Medicina i Ciencies de la Salut, Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat Rovira i Virgili, C./ St. Llorenç 21 43201 Reus (Tarragona), Spain,

Recent studies suggest that the neurobiology of Alzheimer's disease (AD) pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, the scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. Accordingly, alternative hypothesis propose a link between AD and peripheral metabolic alteration. Then, we review in depth changes related to insulin signalling and energy metabolism in the context of the APPSwe/PS1dE9 (APP/PS1) mice model of AD. We show an integrated view of the changes that occur in the early stages of the amyloidogenic process in the APP/PS1 double transgenic mice model. These early changes affect several key metabolic processes related to glucose uptake and insulin signalling, cellular energy homeostasis, mitochondrial biogenesis and increased Tau phosphorylation by kinase molecules like mTOR and Cdk5.
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http://dx.doi.org/10.2741/4372DOI Listing
January 2016

High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents.

Biochim Biophys Acta 2015 Sep 21;1852(9):1687-99. Epub 2015 May 21.

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina de la UB (IBUB), Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Universidad Nacional de Loja, Department of Biotechnology, Ecuador. Electronic address:

Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce β-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age.
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http://dx.doi.org/10.1016/j.bbadis.2015.05.004DOI Listing
September 2015

Ritter reaction-mediated syntheses of 2-oxaadamantan-5-amine, a novel amantadine analog.

Tetrahedron Lett 2015 Mar 31;56(10):1272-1275. Epub 2015 Jan 31.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain.

Two alternative syntheses of 2-oxaadamantan-5-amine, a novel analog of the clinically approved drug amantadine, are reported. The compound has been tested as an anti-influenza A virus agent and as an NMDA receptor antagonist. While the compound was not antivirally active, it displayed moderate activity as an NMDA receptor antagonist.
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http://dx.doi.org/10.1016/j.tetlet.2015.01.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125674PMC
March 2015

Evaluation of okadaic acid, dinophysistoxin-1 and dinophysistoxin-2 toxicity on Neuro-2a, NG108-15 and MCF-7 cell lines.

Toxicol In Vitro 2015 Feb 18;29(1):59-62. Epub 2014 Sep 18.

IRTA, Marine Monitoring Subprogram, Ctra. Poble Nou, Km 5.5, 43540 Sant Carles de la Ràpita, Tarragona, Spain. Electronic address:

Marine dinoflagelates from the genus Dynophisis are important producers of Diarrhetic Shellfish Poisoning (DSP) toxins which are responsible for human intoxications. The present work is an approach to study the relative toxicity of DSP toxins effects on Neuro-2a, NG108-15 and MCF-7 cell-lines. Certified standards of okadaic acid (OA), dinophysistoxin-1 (DTX-1) and dinophysistoxin-2 (DTX-2) were used. Our results show that the three toxins exhibit similar cytotoxicity in Neuro-2a and NG108-15 cell lines. Conversely, MCF-7 cells were the least sensitive to these toxins. DTX-1 displayed the most toxic effect in the three tested cell lines.
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http://dx.doi.org/10.1016/j.tiv.2014.09.002DOI Listing
February 2015

Tryptophanol-derived oxazolopiperidone lactams: identification of a hit compound as NMDA receptor antagonist.

Bioorg Med Chem Lett 2014 Aug 11;24(15):3333-6. Epub 2014 Jun 11.

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address:

N-Methyl-D-aspartate receptors (NMDAR) exacerbated activation leads to neuron death through a phenomenon called excitotoxicity. These receptors are implicated in several neurological diseases (e.g., Alzheimer and Parkinson) and thus represent an important therapeutic target. We herein describe the study of enantiopure tryptophanol-derived oxazolopiperidone lactams as NMDA receptor antagonists. The most active hit exhibited an IC50 of 63.4 μM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than clinically approved NMDA antagonist amantadine (IC50=92 μM).
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http://dx.doi.org/10.1016/j.bmcl.2014.05.105DOI Listing
August 2014

Novel benzopolycyclic amines with NMDA receptor antagonist activity.

Bioorg Med Chem 2014 May 24;22(9):2678-83. Epub 2014 Mar 24.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain. Electronic address:

A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer's approved drug.
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http://dx.doi.org/10.1016/j.bmc.2014.03.025DOI Listing
May 2014

Synthesis of benzopolycyclic cage amines: NMDA receptor antagonist, trypanocidal and antiviral activities.

Bioorg Med Chem 2012 Jan 2;20(2):942-8. Epub 2011 Dec 2.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal, 643, Barcelona E-08028, Spain.

The synthesis of several 6,7,8,9,10,11-hexahydro-9-methyl-5,7:9,11-dimethano-5H-benzocyclononen-7-amines is reported. Several of them display low micromolar NMDA receptor antagonist and/or trypanocidal activities. Two compounds are endowed with micromolar anti vesicular stomatitis virus activity, while only one compound shows micromolar anti-influenza activity. The anti-influenza activity of this compound does not seem to be mediated by blocking of the M2 protein.
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http://dx.doi.org/10.1016/j.bmc.2011.11.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353318PMC
January 2012

Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases.

Curr Pharm Des 2011 ;17(3):230-45

Unitat de Farmacología, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain.

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other neurodegenerative diseases.
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http://dx.doi.org/10.2174/138161211795049732DOI Listing
September 2011

Prosurvival role of JAK/STAT and Akt signaling pathways in MPP+-induced apoptosis in neurons.

Neurochem Int 2010 Dec 9;57(7):774-82. Epub 2010 Sep 9.

Institut de Biomedicina (IBUB), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.

In the present study the role of JAK/STAT and Akt in apoptosis was evaluated in cerebellar granule cells after treatment with the mitochondrial toxin MPP(+). Firstly, we evaluated the role of the prosurvival Akt pathway in MPP(+)-induced apoptosis and found that MPP(+) rapidly reduced the phosphorylation of Akt at Ser473. Since PTEN is an upstream regulator of Akt, its inhibition with bpV(pic) (1-30 μM) should activate Akt, however, it did not attenuate CGC cell death mediated by MPP(+) but protected CGC from apoptosis mediated by S/K deprivation. We also demonstrated that after the treatment with the complex I inhibitor, the expression levels of STAT1 increased and the levels of STAT3 decreased at the time points tested (0.5-8h). Meanwhile, pharmacological inhibition of the JAK/STAT pathway with AG490 (10-40 μM) was neuroprotective, probably due to its antioxidant properties, the Jak2-inhibitor-II potentiated MPP(+) neurotoxicity. Collectively, our data indicate that the treatment of CGC with the neurotoxin MPP(+) decreased two prosurvival pathways: STAT3 and Akt. Meanwhile Akt activation, using a PTEN inhibitor, did not play a prominent role in neuroprotection; loss of STAT3 could be a signal pathway involved in neuroprotection against the Parkinsonian neurotoxin MPP(+).
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http://dx.doi.org/10.1016/j.neuint.2010.08.015DOI Listing
December 2010

Sirtuin activators: designing molecules to extend life span.

Biochim Biophys Acta 2010 Oct-Dec;1799(10-12):740-9. Epub 2010 Jun 23.

Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.

Resveratrol (RESV) exerts important pharmacological effects on human health: in addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it also modulates neuronal energy homeostasis and shows antiaging properties. Although it clearly has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of major interest concerns the effects of RESV on the activity of sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase that has been implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the antiaging properties of RESV, which increases life span in various organisms ranging from yeast to rodents. In addition, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidaemias or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, which are currently undergoing clinical trials, could be potential drugs for the treatment of type 2 diabetes, obesity, and metabolic syndrome, among other disorders. This review summarises current knowledge about the biological functions of SIRT1 in aging and aging-associated diseases and discusses its potential as a pharmacological target.
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http://dx.doi.org/10.1016/j.bbagrm.2010.06.005DOI Listing
February 2011

Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease.

Cell Mol Life Sci 2010 Nov 26;67(22):3865-82. Epub 2010 May 26.

Institut de Biomedicina, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universitat de Barcelona, Spain.

In the present study we demonstrated that neurotoxin MPP(+)-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP(+)-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson's disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G(0)/G(1) cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP(+) leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP(+) and cell-cycle re-entry through retinoblastoma protein phosphorylation.
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http://dx.doi.org/10.1007/s00018-010-0408-5DOI Listing
November 2010

New oxapolycyclic cage amines with NMDA receptor antagonist and trypanocidal activities.

Bioorg Med Chem 2010 Jan 14;18(1):46-57. Epub 2009 Nov 14.

Laboratori de Química Farmacèutica, Unitat Associada al CSIC, Facultat de Farmàcia, and Institute of Biomedicine, Universitat de Barcelona, Av Diagonal, 643, Barcelona E-08028, Spain.

The synthesis of several (1,2,3,5,6,7-hexahydro-1,5:3,7-dimethano-4-benzoxonin-3-yl)amines and related compounds is reported. Several of them display very similar activity to memantine as NMDA receptor antagonists. Several derivatives showed a significant level of trypanocidal activity.
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http://dx.doi.org/10.1016/j.bmc.2009.11.017DOI Listing
January 2010

Evaluation of transcriptional activity of caspase-3 gene as a marker of acute neurotoxicity in rat cerebellar granular cells.

Toxicol In Vitro 2010 Mar 6;24(2):465-71. Epub 2009 Oct 6.

Unitat de Bioquimica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus, Tarragona, Spain.

Caspase-3 is a key protein involved in the classical apoptosis mechanism in neurons, as in many other cells types. In the present research, we describe the transcriptional activity of caspase-3 gene as a marker of acute toxicity in a primary culture model of rat cerebellar granule neurons (CGNs). CGNs were incubated for 16h in complete medium containing the chemicals at three concentrations (10, 100microM and 1mM). A total of 48 different compounds were tested. Gene transcriptional activity was determined by low-density array assays, and by single Taqman caspase-3 assays. Results from the PCR arrays showed that the caspase-3 gene was up-regulated when CGNs were exposed to neurotoxic chemicals. Significative correlations were found between the transcriptional activity of caspase-3 and the activity of some other genes related to apoptosis, cell-cycle and ROS detoxification. In our experiments, acute exposure of CGNs to well-documented pro-apoptotic xenobiotics modulated significantly caspase-3 gene expression, whereas chemicals not related to apoptosis did not modify caspase-3 gene expression. In conclusion, acute exposure of CGNs to neurotoxic compounds modulates the transcriptional activity of genes involved in the classical apoptotic pathway, oxidative stress and cell-cycle control. Transcriptional activity of caspase-3 correlates significantly with these changes and it could be a good indicator of acute neurotoxicity.
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http://dx.doi.org/10.1016/j.tiv.2009.09.023DOI Listing
March 2010

Evaluation of pathways involved in pentachlorophenol-induced apoptosis in rat neurons.

Neurotoxicology 2009 May 10;30(3):451-8. Epub 2009 Feb 10.

Unitat de Bioquimica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C./St. Llorenç 21, 43201 Reus (Tarragona), Spain.

Pentachlorophenol (PCP) (C(6)HCl(5)O) is a synthetic toxic organochloride fungicide for humans which exhibit neurotoxic properties. In the present research, we describe the potential pathways implicated in PCP-induced apoptosis in an acute model of toxicity in rat cerebellar granule neurons (CGNs). In our experiments, acute exposure of CGNs to micromolar concentrations of PCP induced the transcriptional activity of genes related to the classical apoptosis pathway (caspase 3, caspase 8, Bad), oxidative stress and glutathione metabolism (glutathione peroxidase-1, catalase, glutathione-S-transferase-3 and superoxide dismutase-1), and mitogenic response (cyclin D1, cdk2, cdk4, cdkn2b). Results from Western blot also shown significative increases in the expression of cyclins D1, E and A and cdk4. The mitogenic response was also related to a significative increase in the phosphorylation of retinoblastoma protein (Rb). PCP would cause apoptosis up-regulating the transcriptional activity of p53 gene and also increasing their activation by phosphorylation, concomitant with a decrease in the sirtuin 1 content. In conclusion, acute exposure of CGNs to PCP induces the classical p53 apoptotic pathway, promotes the up-regulation of several genes related to oxidative stress and the over-expression of molecules involved in the cell cycle control.
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http://dx.doi.org/10.1016/j.neuro.2009.02.001DOI Listing
May 2009

Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines.

Bioorg Med Chem 2009 Apr 13;17(8):3198-206. Epub 2009 Feb 13.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal, 643, Barcelona E-08028, Spain.

The synthesis of several (2-oxaadamant-1-yl)amines is reported. They were evaluated as NMDA receptor antagonists and several of them were more active than amantadine, but none was more potent than memantine. None of the tested compounds displayed antiviral activity. Two of the derivatives showed a significant level of trypanocidal activity.
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http://dx.doi.org/10.1016/j.bmc.2009.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217223PMC
April 2009

Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs.

Bioorg Med Chem 2008 Dec 17;16(23):9925-36. Epub 2008 Oct 17.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal, 643, Barcelona E-08028, Spain.

The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopamine uptake were also assessed.
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http://dx.doi.org/10.1016/j.bmc.2008.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125889PMC
December 2008

Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues.

Bioorg Med Chem Lett 2008 Dec 5;18(23):6156-60. Epub 2008 Oct 5.

Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, GR-15771 Athens, Greece.

The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.
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http://dx.doi.org/10.1016/j.bmcl.2008.10.003DOI Listing
December 2008

DNA low-density array analysis of colchicine neurotoxicity in rat cerebellar granular neurons.

Neurotoxicology 2008 Mar 31;29(2):309-17. Epub 2007 Dec 31.

Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.

Cytoskeletal alteration is a key factor in neurodegenerative processes like Alzheimer's or Parkinson's disease. Colchicine is a microtubule-disrupting agent that binds to tubuline, inhibiting microtubule assembly, and which triggers apoptosis. The present research describes the transcriptional activation of molecules related to alternative forms of apoptosis, in an acute colchicine model of apoptosis in rat cerebellar granule neurons (CGNs). Treatment with colchicine up-regulated significantly the activity of genes related to oxidative stress: glutathione peroxidase 1 and catalase; altered significantly genes related to cell cycle control (cyclin D1 and cyclin-dependent kinase 2), genes related to classical apoptosis pathway (caspase 3) and a neuronal cell-related gene (pentraxin 1). Colchicine treatment also down-regulated the gene expression of calpain 1. In conclusion, our experiments demonstrate that the cell damage caused by exposure to colchicine activates the classical apoptosis pathway, but also promotes the up-regulation of several genes related to oxidative stress and cell cycle control. Present data may help to a better understanding of the molecular mechanisms involved in cytoskeletal degradation-induced apoptosis in neurons.
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http://dx.doi.org/10.1016/j.neuro.2007.11.007DOI Listing
March 2008

Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8.

J Pineal Res 2007 Apr;42(4):394-402

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia and Institut de Biomedicina, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.

Certain effects of melatonin on senescence were investigated. The experimental model used was 10-month-old senescence-accelerated mouse prone 8 (SAMP8). The mice in the experiment were administered melatonin (10 mg/kg) from the age of 1 month. Results showed that chronic administration of melatonin decreased cell loss in the cerebral cortex and reduced oxidative damage in protein and lipids. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in hyperphosphorylation of tau during aging and neurodegenerative diseases. Melatonin not only reduced the cerebral aging disturbances, but also prevented tau hyperphosphorylation present in the experimental model used in this study. Melatonin reduced cdk5 expression, as well as the cleavage of p35 to p25. The other tau kinase studied, GSK3beta, showed a reduction in this activity in comparison with SAMP8 nontreated SAMP8. These data indicate that melatonin possesses neuroprotective properties against cerebral damage gated to senescence. Moreover, these data suggest that the cdk5/GSKbeta signaling cascade has a potential role as a target for neurodegenerative diseases related to aging.
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http://dx.doi.org/10.1111/j.1600-079X.2007.00433.xDOI Listing
April 2007

Changes in oxidative stress parameters and neurodegeneration markers in the brain of the senescence-accelerated mice SAMP-8.

Exp Gerontol 2006 Apr 20;41(4):360-7. Epub 2006 Mar 20.

Unitat de Farmacologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, c./St. Llorenç 21, E-43201 Reus, Tarragona, Spain.

The senescence-accelerated strains of mice (SAMP) are well-characterized animal models of senescence. Senescence may be related to enhanced production or defective control of reactive oxygen species, which lead to neuronal damage. Therefore, the activity of various oxidative-stress related enzymes was determined in the cortex of 5 months-old senescence-accelerated mice prone-8 (SAMP-8) of both sexes and compared with senescence-accelerated mice-resistant-1 (SAMR-1). Glutathione reductase and peroxidase activities in SAMP-8 male mice were lower than in male SAMR-1, and a decreased catalase activity was found in both male and female SAMP-8 mice, which correlates with the lower catalase expression found by Western blotting. Nissl staining showed marked loss of neuronal cells in the cerebral cortex of five month-old SAMP-8 mice. SAMP-8 mice also had marked astrogliosis and microgliosis. We also found an increase in caspase-3 and calpain activity in the cortex. In addition, we observed morphological changes in the immunostaining of tau protein in SAMP-8, indicative of a loss of their structural function. Altogether, these results show that, at as early as 5 months of age, SAMP-8 mice have cytological and molecular alterations indicative of neurodegeneration in the cerebral cortex and suggestive of altered control of the production of oxidative species and hyper-activation of calcium-dependent enzymes.
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http://dx.doi.org/10.1016/j.exger.2006.01.015DOI Listing
April 2006

Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM).

Mech Ageing Dev 2005 Dec 19;126(12):1300-4. Epub 2005 Sep 19.

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

Tau is a neuronal microtubule-associated protein found predominantly on axons. Tau phosphorylation regulates both normal and pathological functions of this protein. Hyperphosphorylation impairs the microtubule binding function of tau, resulting in the destabilization of microtubules in brain, ultimately leading to the degeneration of the affected neurons. Numerous serine/threonine kinases, including GSK-3beta and Cdk5 can phosphorylate tau. SAMR1 and SAMP8 are murine strains of senescence. We show an increase in hyperphosphorylated forms of tau in SAMP8 (senescent mice) in comparison with resistant strain SAMR1. Moreover, an increase in Cdk5 expression and activation is described but analysis of GSK3beta isoforms failed to show differences in SAMP8 in comparison to age-matched SAMR1. In conclusion, tau hyperphosphorylation occurs in SAMP-8 (early senescent) mice, indicating a link between aging and tau modifications in this murine model.
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http://dx.doi.org/10.1016/j.mad.2005.07.008DOI Listing
December 2005