Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease

Sebastián-Serrano, Álvaro; Diego-García, Laura de; Martínez-Frailes, Carlos; Ávila, Jesús; Zimmermann, Herbert; Millán, José Luis; Miras-Portugal, Marı́a Teresa; Dı́az-Hernández, Miguel

doi:10.1016/j.csbj.2014.12.004

Cited by 56 publications

(39 citation statements)

References 82 publications

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“…One was an intronic variant in ALPL , associated with CpG sites near enhancers in the gene and transcription sites in NBPF3 (Table S5 and Figure S3.1). ALPL encodes an alkaline phosphatase that mediates bone mineralization, regulates cell migration, neuronal differentiation early during development, and post-natal synaptogenesis in transgenic mouse models 45 . Recent reports suggest that ALPL helps propagate the neurotoxicity induced by tau 46 , and its activity increases in Alzheimer’s disease 47 and cognitive impairment 48 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Satizábal

Adams

Hibar

et al. 2017

Preprint

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Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

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Section: Discussionmentioning

confidence: 99%

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Satizábal

Adams

Hibar

et al. 2017

Preprint

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“…In the extracellular space, ATP is released as a co-transmitter or in response to cellular insult (e.g. inflammation, cellular stress or excitotoxicity) (Ballarin et al, 1991;Engler, 1991;Latini and Pedata, 2001) and can be dephosphorylated by ectonucleoside triphosphate diphosphohydrolases (CD39 family) and either ecto-5′-nucleotidase (CD73) (Robson et al, 2006;Bonan, 2012) or by tissue-nonspecific alkaline phosphatase (Sebastian-Serrano et al, 2015) to form extracellular adenosine (Figure 1). Adenosine generation is therefore tightly coupled to the availability of ATP and ADP in the intracellular and extracellular spaces.…”

Section: Tables Of Linksmentioning

confidence: 99%

Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics

Janes

Symons-Liguori

Jacobson

et al. 2016

British J Pharmacology

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Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A 1 , A 2A , A 2B and A 3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A 1 and A 2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A 3 receptor is only in its infancy, but exciting preclinical observations of A 3 receptor antinociception, which have been bolstered by clinical trials of A 3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A 3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A 3 receptor on pain pathways and examine the current state of selective A 3 receptor agonists used for these studies. The adenosine-to-A 3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain. AbbreviationsADA, adenosine deaminase; ADK, adenosine kinase; CCI, chronic constriction injury; CIPN, chemotherapy-induced peripheral neuropathy; CPP, conditioned place preference; ENT, equilibrative nucleoside transporter; PN, peroxynitrite; RVM, rostral ventromedial medulla; SO, superoxide; TLR4, toll-like receptor 4 BJP IntroductionChronic pain afflicts an estimated 10% of the world's adult population (Goldberg and McGee, 2011). The current therapeutic approaches for chronic pain include but are not limited to the use of nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants and opioid pain relievers; however, these strategies are frequently either inadequate or are associated with side effects that reduce quality of life or result in the discontinuation of therapy (Goldberg and McGee, 2011;Pizzo and Clark, 2012). The search for new therapeutic targets is therefore of great importance. Adenosine and two of its associated adenosine receptor subtypes, the A 1 and the A 2A receptor, have been investigated in the field of pain with varying degrees of success; however, these agents lack a useful therapeutic index due to cardiovascular side effects. In response, the focus of research has turned to the previously overlooked A 3 receptor, which displays both preclinical antinociceptive properties (Yoon et al., 2004;Janes et al., 2014bJanes et al., , 2015Ford et al., 2015;Little et al., 2015) and, in trials for non-pain conditions including psoriasis, hepatitis, rheumatoid arthritis, and glaucoma, offers a therapeutic index and tolerability that would be suitable for ...

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“…A number of Alzheimer's disease patients have indicated considerable elevated TNAP activity in the hippocampus section of brain. TNAP can therefore be explored as a potential target for treatment of neurological disorders …”

Section: Introductionmentioning

confidence: 99%

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi

Nazir

Ur-Rehman

et al. 2019

Archiv der Pharmazie

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Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide (3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k) with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.

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Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease

Cited by 56 publications

References 82 publications

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

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Tissue-nonspecific Alkaline Phosphatase Regulates Purinergic Transmission in the Central Nervous System During Development and Disease

Cited by 56 publications

References 82 publications

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Identification of A3 adenosine receptor agonists as novel non‐narcotic analgesics

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

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Identification of A₃ adenosine receptor agonists as novel non‐narcotic analgesics