Quantitative autoradiographic analysis of muscarinic cholinergic and adenosine A1 binding sites after transient forebrain ischemia in the gerbil

Oda, Hiroshi; Sato, Gen; Kogure, Kyuya

doi:10.1016/0006-8993(87)90213-7

Cited by 106 publications

(21 citation statements)

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“…Extracellular ADO rapidly accumulates in the mammalian brain during experimental hypoxia [76] and focal ischaemia [77] serving as a natural defence mechanism to limit ischaemic damage [78,79]. Consistent with this role of ADO, there is experimental evidence in both focal and global ischaemia animal models that direct acting ADO receptor agonists reduce cerebral ischaemic damage while ADO receptor antagonists exacerbate ischaemic trauma [77,80].…”

Section: Cerebral Ischaemiamentioning

confidence: 93%

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Therapeutic potential of adenosine kinase inhibitors

Kowaluk

Jarvis

2000

Expert Opinion on Investigational Drugs

119

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Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra and extracellular concentrations of adenosine (ADO), an endogenous modulator of intercellular signalling that reduces cell excitability during tissue stress and trauma. The inhibitory effects of ADO are mediated by interactions with specific cell-surface G-protein coupled receptors (GPCR), which regulate membrane cation flux, membrane polarisation and the release of excitatory neurotransmitters. Inhibition of AK potentiates local extracellular ADO levels at cell and tissue sites which are undergoing accelerated ADO release. Thus, AK inhibition represents a mechanism to selectively enhance the endogenous protective actions of ADO during cellular stress while potentially minimising the non-specific effects associated with the systemic administration of ADO receptor agonists. Novel, potent AK inhibitors have recently been synthesised that demonstrate high specificity for this particular enzyme as compared to other ADO metabolic enzymes, transporters and receptors. AK inhibitors have been shown to increase ADO concentrations in various systems in vitro, as well as in an in vivo model of neurotoxicity. In addition, AK inhibitors have demonstrated efficacy in animal models of epilepsy, cerebral ischaemia as well as pain and inflammation, thus suggesting their potential therapeutic utility for these conditions.

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Section: Cerebral Ischaemiamentioning

confidence: 93%

“…The neuroprotective effects of ADO are mediated by several distinct but complementary mechanisms [77,78]. As discussed above (section 4.1), activation of ADO A 1 receptors stabilises membrane potentials and inhibits neuronal excitability and excitatory amino acid release.…”

Section: Cerebral Ischaemiamentioning

confidence: 99%

Therapeutic potential of adenosine kinase inhibitors

Kowaluk

Jarvis

2000

Expert Opinion on Investigational Drugs

119

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“…These receptors are molecularly classified into five subtypes, and pharmacologically classified into two subtypes (M1 and M2), according to their affinity for pirenzepine (Cortes et al, 1986;Goyal, 1989). A marked decrease of muscarinic cholinergic receptors has been demonstrated to occur in the hippocampus in the gerbil model of 5-min transient forebrain ischemia (Onodera et al, 1987;Hara et al, 1991;Kondo et al, 1999). M1 mRNA levels decrease in the rat CA1 region after ischemia, being minimal at day 7 postischemia (Hsu et al, 1996).…”

Section: Pet Targeting Muscarinic Cholinergic Receptorsmentioning

confidence: 95%

PET imaging of ischemic neuronal death in the hippocampus of living monkeys

et al. 2002

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The aim of the present study was to visualize postischemic hippocampal neuronal death in the living monkey brain, using a high-resolution positron emission tomography (PET) and novel radioligands. In preceding papers, we reported on postischemic hippocampal neuronal death in a model of Japanese monkeys (Macaca fuscata) undergoing a 20-min complete whole-brain ischemia. Using the same model here, we investigated the in vivo bindings of two radiotracers, [11C]Ro15-4513 (a type II benzodiazepine receptor ligand) and [11C](+)3-MPB (a muscarinic cholinergic receptor ligand), in the hippocampus on day 7 after ischemia, as compared to the normal hippocampus. A significant decrease in the in vivo binding of [11C]Ro154513 and [11C(+)3-MPB was observed in the postischemic monkey hippocampus on day 7 after ischemia compared to controls. Light and electron microscopic analyses of postischemic CA1 neurons showed typical features of coagulation necrosis, as associated with a marked reduction of postsynaptic densities and presynaptic vesicles. These results suggest that semiquantification of hippocampal neuronal death is possible in the living primate brain using PET, and that the same procedures can be applied for evaluating neuronal cell loss in patients with ischemic injuries and/or dementia.

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“…This can be explained by the downregulation of A 1 receptors evoked by increased extracellular adenosine levels. Accordingly, brain ischemia, which increases extracellular levels of adenosine, produces a longlasting decrease in the density of A 1 receptors in several brain regions (Lee et al 1986;Onodera et al 1987;Nagasawa et al 1994). This down-regulation can be associated with a loss of efficiency of A 1 receptor agonists when applied more than 1 h after hypoxic insult (Sweeney 1997;von Lubitz 1999;de Mendonça et al 2000).…”

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confidence: 99%

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

Castillo

León

Ruiz

et al. 2008

Journal of Neurochemistry

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During hypoxia, extracellular adenosine levels are increased to prevent cell damage, playing a neuroprotective role mainly through adenosine A 1 receptors. The aim of the present study was to analyze the effect of hypoxia in both adenosine A 1 and A 2A receptors endogenously expressed in C6 glioma cells. Two hours of hypoxia (5% O 2 ) caused a significant decrease in adenosine A 1 receptors. The same effect was observed at 6 h and 24 h of hypoxia. However, adenosine A 2A receptors were significantly increased at the same times. These effects were not due to hypoxia-induced alterations in cells number or viability. Changes in receptor density were not associated with variations in the rate of gene expression. Furthermore, hypoxia did not alter HIF-1a expression in C6 cells. However, HIF-3a, CREB and CREM were decreased. Adenosine A 1 and A 2A receptor density in normoxic C6 cells treated with adenosine for 2, 6 and 24 h was similar to that observed in cells after oxygen deprivation. When C6 cells were subjected to hypoxia in the presence of adenosine deaminase, the density of receptors was not significantly modulated. Moreover, DPCPX, an A 1 receptor antagonist, blocked the effects of hypoxia on these receptors, while ZM241385, an A 2A receptor antagonist, was unable to prevent these changes. These results suggest that moderate hypoxia modulates adenosine receptors and cAMP response elements in glial cells, through a mechanism in which endogenous adenosine and tonic A 1 receptor activation is involved.

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Quantitative autoradiographic analysis of muscarinic cholinergic and adenosine A1 binding sites after transient forebrain ischemia in the gerbil

Cited by 106 publications

References 50 publications

Therapeutic potential of adenosine kinase inhibitors

Therapeutic potential of adenosine kinase inhibitors

PET imaging of ischemic neuronal death in the hippocampus of living monkeys

Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

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Quantitative autoradiographic analysis of muscarinic cholinergic and adenosine A1 binding sites after transient forebrain ischemia in the gerbil

Cited by 106 publications

References 50 publications

Therapeutic potential of adenosine kinase inhibitors

Therapeutic potential of adenosine kinase inhibitors

PET imaging of ischemic neuronal death in the hippocampus of living monkeys

Modulation of adenosine A1 and A2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine

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Product

Resources

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Modulation of adenosine A₁ and A_2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine