Adenosinergic Modulation of Homocysteine‐Induced Seizures in Mice

Marangos, Paul J.; Loftus, Tyler J.; Wiesner, James B.; Lowe, T. E.; Rossi, Ennio C.; Browne, Cliodhna; Gruber, Harry E.

doi:10.1111/j.1528-1157.1990.tb05371.x

Cited by 68 publications

(41 citation statements)

References 19 publications

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“…These antiplatelet effects of acadesine were prevented by pretreatment with the adenosine receptor antagonist, 8-SPT, at a dose that abolished the coronary vasodilator response to adenosine but did not block the antiplatelet activity of aspirin. In the absence of evidence for direct binding of acadesine to adenosine receptors (39), these data support the in vitro results demonstrating an adenosine-mediated action of acadesine.…”

Section: Discussionsupporting

confidence: 78%

Adenosine-mediated inhibition of platelet aggregation by acadesine. A novel antithrombotic mechanism in vitro and in vivo.

Bullough¹,

Zhang²,

Montag³

et al. 1994

J. Clin. Invest.

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Inhibition of platelet aggregation by acadesine was evaluated both in vitro and ex vivo in human whole blood using impedance aggregometry, as well as in vivo in a canine model of platelet-dependent cyclic coronary flow reductions. In vitro, incubation of acadesine in whole blood inhibited ADP-induced platelet aggregation by 50% at 240±60 ,IM.Inhibition of platelet aggregation was time dependent and was prevented by the adenosine kinase inhibitor, 5 '-deoxy 5-iodotubercidin, which blocked conversion of acadesine to its 5 '-monophosphate, ZMP, and by adenosine deaminase. Acadesine elevated platelet cAMP in whole blood, which was also prevented by adenosine deaminase. In contrast, acadesine had no effect on ADP-induced platelet aggregation or platelet cAMP levels in platelet-rich plasma, but inhibition of aggregation was restored when isolated erythrocytes were incubated with acadesine before reconstitution with platelet-rich plasma. Acadesine (100 mg/kg i.v.) administered to human subjects also inhibited platelet aggregation ex vivo in whole blood. In the canine Folts model of platelet thrombosis, acadesine (0.5 mg/kg per mm i.v.) abolished coronary flow reductions, and this activity was prevented by pretreatment with the adenosine receptor antagonist, 8-sulphophenyltheophylline. These results demonstrate that acadesine exhibits antiplatelet activity in vitro, ex vivo, and in vivo through an adenosine-dependent mechanism. Moreover, the in vitro studies indicate that inhibition of platelet aggregation requires the presence of erythrocytes and metabolism of acadesine to acadesine monophosphate (ZMP). (J. Clin. Invest. 1994. 94:1524-1532

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Section: Discussionsupporting

confidence: 78%

Adenosine-mediated inhibition of platelet aggregation by acadesine. A novel antithrombotic mechanism in vitro and in vivo.

Bullough¹,

Zhang²,

Montag³

et al. 1994

J. Clin. Invest.

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“…The beneficial effects of systemic AICAR administration may be mediated by peripheral tissue, such as muscle tissue, and systemic AICAR administration is not beneficial for behavioral performance or neural plasticity in the absence of the muscle expression of AMPK, and oral AICAR administration is sufficient to increase running endurance by nearly 45% in sedentary mice (Narkar et al, 2008). In addition, o1% of AICAR is able to permeate the blood-brain barrier (Marangos et al, 1990), suggesting that the effects of systemic AICAR administration on the formation of spatial memory are likely indirect. Using a classical fear conditioning model, we found that increasing AMPK activity in the CA1 impaired the formation of longterm fear memory.…”

Section: Discussionmentioning

confidence: 99%

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

Han

Luo

Sun

et al. 2015

Neuropsychopharmacol

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Both the formation of long-term memory (LTM) and dendritic spine growth that serves as a physical basis for the long-term storage of information require de novo protein synthesis. Memory formation also critically depends on transcription. Adenosine monophosphateactivated protein kinase (AMPK) is a transcriptional regulator that has emerged as a major energy sensor that maintains cellular energy homeostasis. However, still unknown is its role in memory formation. In the present study, we found that AMPK is primarily expressed in neurons in the hippocampus, and then we demonstrated a time-dependent decrease in AMPK activity and increase in mammalian target of rapamycin complex 1 (mTORC1) activity after contextual fear conditioning in the CA1 but not CA3 area of the dorsal hippocampus. Using pharmacological methods and adenovirus gene transfer to bidirectionally regulate AMPK activity, we found that increasing AMPK activity in the CA1 impaired the formation of long-term fear memory, and decreasing AMPK activity enhanced fear memory formation. These findings were associated with changes in the phosphorylation of AMPK and p70s6 kinase (p70s6k) and expression of BDNF and membrane GluR1 and GluR2 in the CA1. Furthermore, the prior administration of an mTORC1 inhibitor blocked the enhancing effect of AMPK inhibition on fear memory formation, suggesting that this negative regulation of contextual fear memory by AMPK in the CA1 depends on the mTORC1 signaling pathway. Finally, we found that AMPK activity regulated hippocampal spine growth associated with memory formation. In summary, our results indicate that AMPK is a key negative regulator of plasticity and fear memory formation.

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“…Furthermore, since AICAR is not able to effectively cross the blood-brain barrier (Marangos et al, 1990), this increase in hypothalamic AMPK activity may represent a compensatory response to AICAR-induced reductions in blood glucose.…”

Section: Discussionmentioning

confidence: 99%