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Cherif O.,University of Sfax | Allouche F.,University of Sfax | Chabchoub F.,University of Sfax | Chioua M.,CSIC - Institute of Polymer Science and Technology | And 8 more authors.
Future Medicinal Chemistry

Background: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease. Results: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8-tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 ± 1.12 μM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity analysis. Conclusion: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease. © 2014 Future Science Ltd. Source

Carrera I.,EuroEspes Biotechnology | Etcheverria I.,EuroEspes Biotechnology | Li Y.,Texas A&M University-Kingsville | Fernandez-Novoa L.,EuroEspes Biotechnology | And 6 more authors.
BioMed Research International

APP/PS1 double-transgenic mouse models of Alzheimer's disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β1-42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice. © 2013 Iván Carrera et al. Source

Cacabelos R.,Institute for CNS Disorders and Genomic Medicine | Hashimoto R.,Osaka University | Takeda M.,Osaka University
Psychiatry and Clinical Neurosciences

Central nervous system disorders are the third greatest health problem in developed countries, and schizophrenia represents some of the most disabling ailments in young individuals. There is an abuse and/or misuse of antipsychotics, and recent advances in pharmacogenomics pose new challenges for the clinical management of this complex disorder. Schizophrenia is a multi-factorial/polygenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Consequently, structural and functional genomic changes induce proteomic and metabolomic defects associated with the disease phenotype. Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. About 20% of Caucasians are defective in CYP2D6 enzymes, which participate in the metabolism of 25-30% of central nervous system drugs. Approximately 40% of antipsychotics are substrates of CYP2D6 enzymes, 23% are substrates of CYP3A4, and 18% are substrates of CYP1A2. In order to achieve a mature discipline of pharmacogenomics of schizophrenia it would be effective to accelerate: (i) the education of physicians and the public in the use of genomic screening in daily clinical practice; (ii) the standardization of genetic testing for major categories of drugs; (iii) the validation of pharmacogenomic procedures according to drug category and pathology; (iv) the regulation of ethical, social, and economic issues; and (v) the incorporation of pharmacogenomic procedures of drugs in development and drugs on the market in order to optimize therapeutics. © 2011 Japanese Society of Psychiatry and Neurology. Source

Cacabelos R.,Institute for CNS Disorders and Genomic Medicine | Cacabelos R.,Camilo Jose Cela University | Martinez-Bouza R.,Institute for CNS Disorders and Genomic Medicine
CNS Neuroscience and Therapeutics

Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics. © 2010 Blackwell Publishing Ltd. Source

Romero A.,Complutense University of Madrid | Cacabelos R.,Institute for CNS Disorders and Genomic Medicine | Oset-Gasque M.J.,Complutense University of Madrid | Samadi A.,Institute of General Organic Chemistry CSIC | Marco-Contelles J.,Institute of General Organic Chemistry CSIC
Bioorganic and Medicinal Chemistry Letters

A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimer's disease is presented. © 2013 Elsevier Ltd. All rights reserved. Source

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