Adenosine A1 and A3 receptors protect astrocytes from hypoxic damage

Björklund, Olga; Shang, Mei; Tonazzini, Ilaria; Daré, Elisabetta; Fredholm, Bertil B.

doi:10.1016/j.ejphar.2008.08.002

Cited by 85 publications

(70 citation statements)

References 45 publications

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“…Their effectiveness at micromolar concentrations presents significant therapeutic potential without the side effects of metal toxicity. Our findings also have strong implications for the current use of high (200 -500 M) levels of CoCl 2 for experimental modeling of hypoxia (25)(26)(27). In those studies it is frequently assumed that cobalt ions simulate hypoxic stress by direct activation of the promoter elements of HIF1-␣ gene or by redox activity of excess Co II causing reactive oxygen species production.…”

Section: Discussionmentioning

confidence: 64%

Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes

Schieber

Howitt

Putz

et al. 2011

Journal of Biological Chemistry

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The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [ Transition metals are essential for many important chemical processes in biological systems. Most of these metal-related processes occur by interactions with nucleic acids and proteins. Within the cell, metal ions can stabilize, destabilize, or modulate DNA and proteins by introducing conformational changes and by creating centers of activity. Although the use of metals as structural elements within the cell is well known, emerging evidence now recasts metals as signaling molecules able to activate critical cellular pathways. For example, metals such as iron, copper, and cobalt can produce reactive oxygen species that lead to the activation of redox-sensitive transcription factors including NF-B, AP-1, and p53. Metals have also been suggested to affect the upstream regulatory components of the MAP kinase and the PI3K/Akt/mTor pathway (1, 2). Thus the levels and regulation of metals in a cell can have a direct role on cell function and survival.Metal ions such as Co II and Fe II can stimulate the expression of the neuroprotective protein Nedd4 family interacting protein 1 (Ndfip1) 4 in the brain (3). Ndfip1 is a transmembrane protein that is localized to the Golgi and post-Golgi vesicles such as endosomes (4, 5). Ndfip1 functions as an adaptor protein for the Nedd4 family of ubiquitin ligases that target proteins for both degradation and trafficking (4). The metal-induced up-regulation of Ndfip1 results in the activation of the ubiquitin proteasome pathway. Ndfip1 recognizes and interacts with divalent metal transporter 1 (DMT1), this recruits the E3 ligase Nedd4 -2 resulting in degradation of DMT1, preventing iron overload within the cell (3). Other targets for Ndfip1 have also been identified, including the transcription factor JunB that is regulated by Ndfip1 in association with the E3 ligase Itch (6). In the adult brain, Ndfip1 is endogenously present in cortical neurons at low levels, however it is up-regulated in a subset of neurons upon activation by injury or stress (7). Importantly, this up-regulation of Ndfip1 has been shown to be neuroprotective, and neurons with up-regulated Ndfip1 do not undergo apoptosis.Whereas high levels of exogenous Co II and Fe II are toxic to cells, our previous results show they also stimulate Ndfip1 via still unknown mechanisms. Barring the effects of metal toxicity, this finding introduces an opportunity to harness the capacity of metal ions to up-regulate Ndfip1 for neuroprotective purposes. In the present study, we investigate the utility of nontoxic metal complexes for controlled intracellular delivery of cobalt to stimulate Ndfip1 expression. This was based on the premise that the reactivity of metal ions can be modulated by the formation of coordination complexes, with a complexed 4 The abbreviations used are: Ndfip1, Nedd4 family interacting protein 1; DMT1, divalent metal transporte...

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Section: Discussionmentioning

confidence: 64%

Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes

Schieber

Howitt

Putz

et al. 2011

Journal of Biological Chemistry

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“…Supporting these results Bjorklund et al [25] found that both A1 and A3 adenosine receptors were implicated in protecting astrocytes from injury. Thus, adenosine is a protector of brain astrocytes through the activation of A1 and A3 receptors.…”

Section: Adenosine Astrocytes and Seizuresmentioning

confidence: 69%

Purinergic Mechanisms in Epilepsy

Dragunow¹

2010

TONEURJ

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Adenosine is a powerful neuromodulator that has a range of functions in various cells and tissues throughout the body. In the brain adenosine controls many varied processes through a range of receptors. Research over the past 25 years has implicated adenosine, acting predominantly through the A1 receptor, in seizure control and epilepsy. Most of this work has utilized animal models and there are still only a handful of studies in humans. In this article, I will focus on specific aspects of the role of adenosine in epilepsy, in particular its role in terminating seizures and preventing status epilepticus, a prolonged and neurologically dangerous seizure state. I will also discuss the few reports that have studied adenosine in human epilepsy in an attempt to bridge the gap between pre-clinical studies and the clinic. The great challenge for researchers is to translate knowledge about adenosine and epilepsy from the lab to the clinic to develop new medications to treat people suffering from epilepsy and status epilepticus.Keywords: Adenosine, Seizure arrest, status epilepticus, human epilepsy.Adenosine is a powerful neuromodulator that has a range of functions in various cells and tissues throughout the body. In the brain adenosine controls many varied processes through a number of receptors (A1, A2a, A2b, A3). In particular, research over the past 25 years has implicated adenosine in seizure control and epilepsy. Most of this work has utilized animal models and there are still only a handful of studies in humans. Twenty-one years ago I wrote a review article entitled "Purinergic Mechanisms in Epilepsy" which was published in Progress in Neurobiology [1]. At that time there was a growing body of research which suggested very strongly that adenosine played a major role in controlling epileptic seizures although there was controversy regarding the role of basal versus seizure-induced adenosine levels. Many hundreds of studies have been published since that review appeared (a PubMed search using "adenosine and epilepsy" found 607 papers published between 1988 and 2009). In this article I wish to address 3 questions. First, has our understanding of the role of adenosine in epilepsy progressed during this time period and, in particular, are there any human studies that shed further light on the role of adenosine in epilepsy? Second, are we any closer to designing drugs (and/or other therapies) based upon our knowledge of adenosine in epilepsy for people with epilepsy and/or status epilepticus? Finally, how can we facilitate the translation of basic research in this area to the clinic? ADENOSINE AND EPILEPSY -HUMAN STUDIESAlthough there is a vast literature on the role of adenosine in epilepsy using in vivo and in vitro animal models there is a scarcity of data in humans. It is not the intent of this article to review the literature studying adenosine in seizures in animal models. This work has been *Address correspondence to this author at the Department of Pharmacology and the Centre for Brain Research, Facul...

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“…Lastly, given the low affinity of caffeine for the A 3 R, it was surprising to find that caffeine-induced psychomotor activity is reduced in A 3 R KO mice [30]. Since A 3 R KO similarly attenuated both caffeine-and amphetamine-induced psychomotor activity, the possible developmental effect of A 3 R KO (such as compensatory changes in A 1 Rs and A 2A Rs) needs to be taken into consideration [30].…”

Section: Adenosine Receptors and Caffeine Effectsmentioning

confidence: 99%

“…Since A 3 R KO similarly attenuated both caffeine-and amphetamine-induced psychomotor activity, the possible developmental effect of A 3 R KO (such as compensatory changes in A 1 Rs and A 2A Rs) needs to be taken into consideration [30].…”

Section: Adenosine Receptors and Caffeine Effectsmentioning

confidence: 99%

What Knock-Out Animals Tell Us About the Effects of Caffeine

Chen

Shen

et al. 2010

JAD

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Abstract.Caffeine is well known for its complex pharmacological actions, in part reflecting the multiple molecular targets of caffeine. The adenosine receptors are the primary extracellular targets of caffeine. Since caffeine has similar affinity for several adenosine receptors, it has been difficult to determine which receptor subtypes mediate caffeine's effects using pharmacological tools. The development of genetic mutant mice deficient in adenosine receptors and other signaling molecules has allowed targeted inquiry into the molecular targets by which caffeine elicits its biological effects on behavior and gene expression. This review summarizes recent work using genetic knockout models to elucidate the mechanisms of caffeine action in the brain. This review focuses on insights into caffeine action from genetic knockout models on: (1) the molecular basis for caffeine's effects on psychomotor activity; (2) the involvement of adenosine receptors in caffeine-mediated arousal and cognitive effects; and (3) a novel approach using knockout animals coupled with microarray profiling to validate multiple molecular targets of caffeine in striatal gene expression.

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Adenosine A1 and A3 receptors protect astrocytes from hypoxic damage

Cited by 85 publications

References 45 publications

Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes

Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes

Purinergic Mechanisms in Epilepsy

What Knock-Out Animals Tell Us About the Effects of Caffeine

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