Effects of nitrobenzylthioinosine on adenosine levels and neuronal injury in rat forebrain ischemia

Zhang, Yi Wei; Shepel, P. N.; Peeling, James; Geiger, Jonathan D.; Parkinson, Fiona E.

doi:10.1002/nrc.10020

Cited by 9 publications

(3 citation statements)

References 4 publications

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“…However, a recent study using cocultures of astrocytes and neurons [124] suggests that the extracellular pathway can predominate when both cell types are present. This was also indicated by our previous in vivo stroke studies, which demonstrated a neuroprotective effect of the ENT1 inhibitor prodrug NBMPR 5'-phosphate (NBMPR-P) [87,130,133]. We suggested that the active form of this drug inhibited adenosine release from neurons, and inhibited adenosine uptake into astrocytes.…”

Section: Cerebral Ischemiasupporting

confidence: 62%

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Parkinson¹,

Damaraju²,

Graham³

et al. 2011

CTMC

165

149

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Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.

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Section: Cerebral Ischemiasupporting

confidence: 62%

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Parkinson¹,

Damaraju²,

Graham³

et al. 2011

CTMC

165

149

View full text Add to dashboard Cite

show abstract

“…The beneficial effects of administering the ENT inhibitor dipyridamole during percutaneous transluminal coronary angioplasty in humans are likely to have a similar origin [32]. Transport inhibitors are also potentially of value in the context of ischaemic neuronal injury: pre-ischaemic administration of the pro-drug NBMPR-phosphate has been shown to increase brain adenosine levels and reduce ischaemia-induced loss of hippocampal CA1 neurons in the rat [33]. ENT4 expression is abundant in heart and adenosine transport pH-dependency suggests a contribution to the regulation of extracellular adenosine concentrations during myocardial ischemia.…”

Section: Discussionmentioning

confidence: 99%

Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4)

Wang

Lin

Playa

et al. 2013

Biochemical Pharmacology

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To identify needed human equilibrative nucleoside transporter 4 (hENT4) inhibitors, we cloned and stably expressed the recombinant protein in PK15NTD (nucleoside transporter deficient) cells, and, investigated its interaction with a series of dipyridamole analogues synthesized in our laboratory. Compounds were tested in this newly established hENT4 expressing system as well in previous stably expressed hENT1 and hENT2 expressing systems. Of the dipyridamole analogues evaluated, about one fourth of the compounds inhibited hENT4 with higher potencies than dipyridamole. The most potent of them, Compound 30 displayed an IC50 of 74.4 nM, making it about 38 times more potent than dipyridamole (IC50 = 2.8 μM), and selectivities of about 80-fold and 20-fold relative to ENT1 and ENT2, respectively. Structure-activity relationship showed nitrogen-containing monocyclic rings and noncyclic substituents at the 4-and 8-positions of the pyrimido[5,4-d]pyrimidine were important for the inhibitory activity against hENT4. The most potent and selective hENT4 inhibitors tended to have a 2,6-di(N-monohydroxyethyl) substitution on the pyrimidopyrimidine ring system. The inhibitors of hENT4 identified in this study are the most selective and potent inhibitors of hENT4 adenosine transporter function to date, and should serve as useful pharmacological/biochemical tools and/or potential leads for ENT4-based therapeutics. Also, the new hENT4-expressing PK15 cell line established will serve as a useful screening tool for the discovery and design of hENT4 ligands.

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“…The beneficial effects of administering the ENT inhibitor dipyridamole during percutaneous transluminal coronary angioplasty in humans are likely to have a similar origin [29]. Transport inhibitors are also potentially of value in the context of ischaemic neuronal injury: pre-ischaemic administration of the pro-drug NBMPRphosphate has been shown to increase brain adenosine levels and reduce ischaemia-induced loss of hippocampal CA1 neurons in the rat [55].…”

Section: Pharmacology and Therapeutic Applicationsmentioning

confidence: 98%

The equilibrative nucleoside transporter family, SLC29

Baldwin

Beal

Yao

et al. 2004

Pfl�gers Archiv European Journal of Physiology

596

142

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The human SLC29 family of proteins contains four members, designated equilibrative nucleoside transporters (ENTs) because of the properties of the first-characterised family member, hENT1. They belong to the widely-distributed eukaryotic ENT family of equilibrative and concentrative nucleoside/nucleobase transporters and are distantly related to a lysosomal membrane protein, CLN3, mutations in which cause neuronal ceroid lipofuscinosis. A predicted topology of 11 transmembrane helices with a cytoplasmic N-terminus and an extracellular C-terminus has been experimentally confirmed for hENT1. The best-characterised members of the family, hENT1 and hENT2, possess similar broad substrate specificities for purine and pyrimidine nucleosides, but hENT2 in addition efficiently transports nucleobases. The ENT3 and ENT4 isoforms have more recently also been shown to be genuine nucleoside transporters. All four isoforms are widely distributed in mammalian tissues, although their relative abundance varies: ENT2 is particularly abundant in skeletal muscle. In polarised cells ENT1 and ENT2 are found in the basolateral membrane and, in tandem with concentrative transporters of the SLC28 family, may play a role in transepithelial nucleoside transport. The transporters play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis, and are also responsible for the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases. In addition, by regulating the concentration of adenosine available to cell surface receptors, they influence many physiological processes ranging from cardiovascular activity to neurotransmission.

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Effects of nitrobenzylthioinosine on adenosine levels and neuronal injury in rat forebrain ischemia

Cited by 9 publications

References 4 publications

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4)

The equilibrative nucleoside transporter family, SLC29

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