Medina M

General

Full name : Medina Miguel

First name : Miguel

Mail : Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas

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Country : Spain

Email : mmedina@ciberned.es

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References (11)

Title : Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration - Ramsay_2016_Front.Neurosci_10_375
Author(s) : Ramsay RR , Majekova M , Medina M , Valoti M
Ref : Front Neurosci , 10 :375 , 2016
Abstract : HIGHLIGHTS Compounds that interact with multiple targets but minimally with the cytochrome P450 system (CYP) address the many factors leading to neurodegeneration.Acetyl- and Butyryl-cholineEsterases (AChE, BChE) and Monoamine Oxidases A/B (MAO A, MAO B) are targets for Multi-Target Designed Ligands (MTDL).ASS234 is an irreversible inhibitor of MAO A >MAO B and has micromolar potency against the cholinesterases.ASS234 is a poor CYP substrate in human liver, yielding the depropargylated metabolite.SMe1EC2, a stobadine derivative, showed high radical scavenging property, in vitro and in vivo giving protection in head trauma and diabetic damage of endothelium.Control of mitochondrial function and morphology by manipulating fission and fusion is emerging as a target area for therapeutic strategies to decrease the pathological outcome of neurodegenerative diseases. Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to "dirty drugs" for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson's Disease's (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress toward strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent metabolism of MTDLs.
ESTHER : Ramsay_2016_Front.Neurosci_10_375
PubMedSearch : Ramsay_2016_Front.Neurosci_10_375
PubMedID: 27597816

Title : New perspectives on the role of tau in Alzheimer's disease. Implications for therapy - Medina_2014_Biochem.Pharmacol_88_540
Author(s) : Medina M , Avila J
Ref : Biochemical Pharmacology , 88 :540 , 2014
Abstract : Alzheimer's disease (AD) and related dementias constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of AD, the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists have demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. While drug development efforts in the last two decades have primarily focused on the amyloid cascade hypothesis, so far with disappointing results, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. Abnormal levels and hyperphosphorylation of tau protein have been reported to be the underlying cause of a group of neurodegenerative disorders collectively known as 'tauopathies'. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates and the accumulation of insoluble intracellular neurofibrillary tangles. However, it has become clear in recent years that tau is not only a microtubule interacting protein, but rather has additional roles in cellular processes. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some novel approaches on the verge of providing new treatment paradigms within the coming years.
ESTHER : Medina_2014_Biochem.Pharmacol_88_540
PubMedSearch : Medina_2014_Biochem.Pharmacol_88_540
PubMedID: 24462919

Title : Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study - Del Ser_2013_J.Alzheimers.Dis_33_205
Author(s) : Del Ser T , Steinwachs KC , Gertz HJ , Andres MV , Gomez-Carrillo B , Medina M , Vericat JA , Redondo P , Fleet D , Leon T
Ref : J Alzheimers Dis , 33 :205 , 2013
Abstract : This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 x ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.
ESTHER : Del Ser_2013_J.Alzheimers.Dis_33_205
PubMedSearch : Del Ser_2013_J.Alzheimers.Dis_33_205
PubMedID: 22936007

Title : Recent developments in tau-based therapeutics for neurodegenerative diseases - Medina_2011_Recent.Pat.CNS.Drug.Discov_6_20
Author(s) : Medina M
Ref : Recent Pat CNS Drug Discov , 6 :20 , 2011
Abstract : Neurodegenerative diseases constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of Alzheimer's disease (AD), the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists has demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. Drug development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some targets with significant potential in the field and which might be on the verge of providing new treatment paradigms within the coming years. Among those strategies, immunotherapy approaches will be mostly discussed. An update on 2010 patents regarding different aspects of tau-based therapeutic strategies is also provided.
ESTHER : Medina_2011_Recent.Pat.CNS.Drug.Discov_6_20
PubMedSearch : Medina_2011_Recent.Pat.CNS.Drug.Discov_6_20
PubMedID: 21118095

Title : Potent beta-amyloid modulators - Garcia-Palomero_2008_Neurodegener.Dis_5_153
Author(s) : Garcia-Palomero E , Munoz P , Usan P , Garcia P , Delgado E , de Austria C , Valenzuela R , Rubio L , Medina M , Martinez A
Ref : Neurodegener Dis , 5 :153 , 2008
Abstract : Currently, the potential to interfere with the pathology of beta-amyloid targeting a well-known drugable enzyme, the acetylcholinesterase (AChE), is opened. Peripheral or dual binding site inhibitors of AChE may simultaneously alleviate the cognitive and behavioral deficits in Alzheimer's disease (AD) patients and, more importantly, act as disease-modifying agents delaying amyloid plaque formation. As part of a rational drug design program directed to find dual binding site AChE inhibitors, several families of compounds have been synthesized as potent AChE inhibitors. From these series, several drug candidates were selected based on their potent and selective inhibition of AChE (subnanomolar activity) and their interference with the beta-amyloid aggregation in vitro (IC(50) in the low micromolar range). First in vivo data confirm our initial hypothesis. Oral treatment with NP-61 for 3 months is able to reverse the cognitive impairment (Morris water maze test) and to reduce plaque load in the brains of human amyloid precursor protein transgenic mice (Swedish mutation). These results suggest that NP-61, a potent beta-amyloid modulator, is able to reverse the AD-like neurodegenerative phenotype in transgenic mice, indicating a promising disease-modifying agent for clinical application.
ESTHER : Garcia-Palomero_2008_Neurodegener.Dis_5_153
PubMedSearch : Garcia-Palomero_2008_Neurodegener.Dis_5_153
PubMedID: 18322376

Title : Dual binding site acetylcholinesterase inhibitors: potential new disease-modifying agents for AD - del Monte-Millan_2006_J.Mol.Neurosci_30_85
Author(s) : del Monte-Millan M , Garcia-Palomero E , Valenzuela R , Usan P , de Austria C , Munoz-Ruiz P , Rubio L , Dorronsoro I , Martinez A , Medina M
Ref : Journal of Molecular Neuroscience , 30 :85 , 2006
Abstract : The therapeutic potential of acetylcholinesterase (AChE) inhibitors has been strengthened recently by evidence showing that besides their role in cognitive function, they might contribute to slow down the neurodegeneration in Alzheimer's disease (AD) patients. It is known that AChE exerts secondary noncholinergic functions, related to its peripheral anionic site, in cell adhesion and differentiation, and recent findings also support its role in mediating the processing and deposition of beta-amyloid (Abeta) peptide. AChE is one of the proteins that colocalizes with Abeta peptide deposits in the brain of AD patients and promotes Abeta fibrillogenesis by forming stable AChEA beta complexes. Additionally, it has also been postulated that AChE binds through its peripheral site to the Abeta nonamyloidogenic form and acts as a pathological chaperone inducing a conformational transition to the amyloidogenic form (Inestrosa et al., 1996; Bartolini et al., 2003). Anew series of dual binding site AChE inhibitors has been designed and synthesized as new potent AChE inhibitors, which might simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting Abeta peptide aggregation through binding to both catalytic and peripheral sites of the enzyme.
ESTHER : del Monte-Millan_2006_J.Mol.Neurosci_30_85
PubMedSearch : del Monte-Millan_2006_J.Mol.Neurosci_30_85
PubMedID: 17192640

Title : Phytophthora genome sequences uncover evolutionary origins and mechanisms of pathogenesis - Tyler_2006_Science_313_1261
Author(s) : Tyler BM , Tripathy S , Zhang X , Dehal P , Jiang RH , Aerts A , Arredondo FD , Baxter L , Bensasson D , Beynon JL , Chapman J , Damasceno CM , Dorrance AE , Dou D , Dickerman AW , Dubchak IL , Garbelotto M , Gijzen M , Gordon SG , Govers F , Grunwald NJ , Huang W , Ivors KL , Jones RW , Kamoun S , Krampis K , Lamour KH , Lee MK , McDonald WH , Medina M , Meijer HJ , Nordberg EK , Maclean DJ , Ospina-Giraldo MD , Morris PF , Phuntumart V , Putnam NH , Rash S , Rose JK , Sakihama Y , Salamov AA , Savidor A , Scheuring CF , Smith BM , Sobral BW , Terry A , Torto-Alalibo TA , Win J , Xu Z , Zhang H , Grigoriev IV , Rokhsar DS , Boore JL
Ref : Science , 313 :1261 , 2006
Abstract : Draft genome sequences have been determined for the soybean pathogen Phytophthora sojae and the sudden oak death pathogen Phytophthora ramorum. Oomycetes such as these Phytophthora species share the kingdom Stramenopila with photosynthetic algae such as diatoms, and the presence of many Phytophthora genes of probable phototroph origin supports a photosynthetic ancestry for the stramenopiles. Comparison of the two species' genomes reveals a rapid expansion and diversification of many protein families associated with plant infection such as hydrolases, ABC transporters, protein toxins, proteinase inhibitors, and, in particular, a superfamily of 700 proteins with similarity to known oomycete avirulence genes.
ESTHER : Tyler_2006_Science_313_1261
PubMedSearch : Tyler_2006_Science_313_1261
PubMedID: 16946064
Gene_locus related to this paper: phyrm-h3ga89 , phyrm-h3gbl6.1 , phyrm-h3gbl6.2 , phyrm-h3gbl7 , phyrm-h3gdd4 , phyrm-h3gl36 , phyrm-h3gq42 , phyrm-h3gx86 , phyrm-h3gyi2 , phyrm-h3gyi3 , phyrm-h3gyi4 , phyrm-h3h292 , phyrm-h3h293 , phyrm-h3h967 , phyrm-h3hcf9 , physp-g4ynp3 , physp-g4yut6 , physp-g4yut8 , physp-g4yw23 , physp-g4zis3 , physp-g4zqe3 , physp-g4zqe4 , physp-g4zqf0 , physp-g4zqn9 , physp-g4zwy9 , physp-g5a582 , physp-g5a583 , physp-g5aav9 , phyrm-h3g9e7 , physp-g4zwu9 , phyrm-h3ggp1 , physp-g4ztq5 , physp-g4zwu8 , physp-g4zwv7 , physp-g4zwv6 , physp-g4zwv0 , physp-g4zwv8 , phyrm-h3gp95 , phyrm-h3g6r5 , physp-g4zwv9 , physp-g5a510 , phyrm-h3glu3 , physp-g5aci1 , phyrm-h3h2d0 , physp-g4ztb2 , physp-g4yg47 , phyrm-h3h2c9 , physp-g4ztb3 , phyrm-h3gvj3 , phyrm-h3gy62 , physp-g4yg46 , physp-g4zdt9 , phyrm-h3gdh5 , physp-g4zm41 , physp-g5abj7 , phyrm-h3gz76 , physp-g5a425 , phyrm-h3h080 , physp-g4ytv0 , phyrm-h3gcw7

Title : Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE - Alonso_2005_Bioorg.Med.Chem_13_6588
Author(s) : Alonso D , Dorronsoro I , Rubio L , Munoz P , Garcia-Palomero E , del Monte M , Bidon-Chanal A , Orozco M , Luque FJ , Castro A , Medina M , Martinez A
Ref : Bioorganic & Medicinal Chemistry , 13 :6588 , 2005
Abstract : A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.
ESTHER : Alonso_2005_Bioorg.Med.Chem_13_6588
PubMedSearch : Alonso_2005_Bioorg.Med.Chem_13_6588
PubMedID: 16230018

Title : Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease - Munoz-Ruiz_2005_J.Med.Chem_48_7223
Author(s) : Munoz-Ruiz P , Rubio L , Garcia-Palomero E , Dorronsoro I , del Monte-Millan M , Valenzuela R , Usan P , de Austria C , Bartolini M , Andrisano V , Bidon-Chanal A , Orozco M , Luque FJ , Medina M , Martinez A
Ref : Journal of Medicinal Chemistry , 48 :7223 , 2005
Abstract : New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).
ESTHER : Munoz-Ruiz_2005_J.Med.Chem_48_7223
PubMedSearch : Munoz-Ruiz_2005_J.Med.Chem_48_7223
PubMedID: 16279781

Title : The genome of the diatom Thalassiosira pseudonana: ecology, evolution, and metabolism - Armbrust_2004_Science_306_79
Author(s) : Armbrust EV , Berges JA , Bowler C , Green BR , Martinez D , Putnam NH , Zhou S , Allen AE , Apt KE , Bechner M , Brzezinski MA , Chaal BK , Chiovitti A , Davis AK , Demarest MS , Detter JC , Glavina T , Goodstein D , Hadi MZ , Hellsten U , Hildebrand M , Jenkins BD , Jurka J , Kapitonov VV , Kroger N , Lau WW , Lane TW , Larimer FW , Lippmeier JC , Lucas S , Medina M , Montsant A , Obornik M , Parker MS , Palenik B , Pazour GJ , Richardson PM , Rynearson TA , Saito MA , Schwartz DC , Thamatrakoln K , Valentin K , Vardi A , Wilkerson FP , Rokhsar DS
Ref : Science , 306 :79 , 2004
Abstract : Diatoms are unicellular algae with plastids acquired by secondary endosymbiosis. They are responsible for approximately 20% of global carbon fixation. We report the 34 million-base pair draft nuclear genome of the marine diatom Thalassiosira pseudonana and its 129 thousand-base pair plastid and 44 thousand-base pair mitochondrial genomes. Sequence and optical restriction mapping revealed 24 diploid nuclear chromosomes. We identified novel genes for silicic acid transport and formation of silica-based cell walls, high-affinity iron uptake, biosynthetic enzymes for several types of polyunsaturated fatty acids, use of a range of nitrogenous compounds, and a complete urea cycle, all attributes that allow diatoms to prosper in aquatic environments.
ESTHER : Armbrust_2004_Science_306_79
PubMedSearch : Armbrust_2004_Science_306_79
PubMedID: 15459382
Gene_locus related to this paper: thaps-b5ymy7 , thaps-b5yn04 , thaps-b5ynz7 , thaps-b8bq57 , thaps-b8bsn5 , thaps-b8bsy4 , thaps-b8bv00 , thaps-b8bxb3 , thaps-b8byx0 , thaps-b8bzg5 , thaps-b8c0a3 , thaps-b8c2d8 , thaps-b8c2k9 , thaps-b8c2s5 , thaps-b8c3p0 , thaps-b8c5l7 , thaps-b8c6y7 , thaps-b8c9k8 , thaps-b8c9t6 , thaps-b8c345 , thaps-b8c584 , thaps-b8c885 , thaps-b8c954 , thaps-b8cdd7 , thaps-b8cdt3 , thaps-b8cf07 , thaps-b8cfn8 , thaps-b8c079

Title : The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins - Dehal_2002_Science_298_2157
Author(s) : Dehal P , Satou Y , Campbell RK , Chapman J , Degnan B , De Tomaso A , Davidson B , Di Gregorio A , Gelpke M , Goodstein DM , Harafuji N , Hastings KE , Ho I , Hotta K , Huang W , Kawashima T , Lemaire P , Martinez D , Meinertzhagen IA , Necula S , Nonaka M , Putnam N , Rash S , Saiga H , Satake M , Terry A , Yamada L , Wang HG , Awazu S , Azumi K , Boore J , Branno M , Chin-Bow S , DeSantis R , Doyle S , Francino P , Keys DN , Haga S , Hayashi H , Hino K , Imai KS , Inaba K , Kano S , Kobayashi K , Kobayashi M , Lee BI , Makabe KW , Manohar C , Matassi G , Medina M , Mochizuki Y , Mount S , Morishita T , Miura S , Nakayama A , Nishizaka S , Nomoto H , Ohta F , Oishi K , Rigoutsos I , Sano M , Sasaki A , Sasakura Y , Shoguchi E , Shin-I T , Spagnuolo A , Stainier D , Suzuki MM , Tassy O , Takatori N , Tokuoka M , Yagi K , Yoshizaki F , Wada S , Zhang C , Hyatt PD , Larimer F , Detter C , Doggett N , Glavina T , Hawkins T , Richardson P , Lucas S , Kohara Y , Levine M , Satoh N , Rokhsar DS
Ref : Science , 298 :2157 , 2002
Abstract : The first chordates appear in the fossil record at the time of the Cambrian explosion, nearly 550 million years ago. The modern ascidian tadpole represents a plausible approximation to these ancestral chordates. To illuminate the origins of chordate and vertebrates, we generated a draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome contains approximately 16,000 protein-coding genes, similar to the number in other invertebrates, but only half that found in vertebrates. Vertebrate gene families are typically found in simplified form in Ciona, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development. The ascidian genome has also acquired a number of lineage-specific innovations, including a group of genes engaged in cellulose metabolism that are related to those in bacteria and fungi.
ESTHER : Dehal_2002_Science_298_2157
PubMedSearch : Dehal_2002_Science_298_2157
PubMedID: 12481130
Gene_locus related to this paper: cioin-141645 , cioin-147959 , cioin-150181 , cioin-154370 , cioin-ACHE1 , cioin-ACHE2 , cioin-cxest , cioin-f6qcp0 , cioin-f6r8z1 , cioin-f6u176 , cioin-f6vac9 , cioin-f6x584 , cioin-f6xa69 , cioin-f6y403 , cioin-h2xqb4 , cioin-H2XTI0 , cioin-F6T1M3 , cioin-H2XUP7 , cioin-CIN.7233 , cioin-F6V269 , cioin-Cin16330 , cioin-h2xua2 , cioin-f6vaa5 , cioin-f6v9x6 , cioin-f6swc9 , cioin-f7amz2 , cioin-f6s021 , cioin-h2xxq9 , cioin-h2xne6 , cioin-f6ynr2