Interaction of Afobazole with σ1-Receptors

Seredenin, S. B.; Антипова, Татьяна Алексеевна; Voronin, M. V.; Kurchashova, S. Yu.; Куимов, А. Н.

doi:10.1007/s10517-009-0624-x

Cited by 23 publications

(19 citation statements)

References 7 publications

(5 reference statements)

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“…Activation of receptors has been linked to inhibition of microglial cell migration and afobazole has been suggested to interact with receptors (Seredenin et al, 2009). Experiments were carried out to determine whether afobazole acts through receptors in microglial cells to inhibit migration.…”

Section: Resultsmentioning

confidence: 99%

Afobazole Modulates Microglial Function via Activation of Both σ-1 and σ-2 Receptors

Cuevas¹,

Rodríguez²,

Behensky³

et al. 2011

J Pharmacol Exp Ther

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Microglial cells play a critical role in the neuroinflammatory response that accompanies various diseases of the central nervous system, such as ischemic stroke, and ATP is a major signaling molecule regulating the response of these cells to these pathophysiological conditions. Experiments were carried out to determine the effects of afobazole on microglial function and to identify the molecular mechanisms by which afobazole affects microglial cells. Afobazole was found to inhibit migration of microglial cells in response to ATP and UTP chemoattraction in a concentration-dependent manner. Inhibition of either -1 or -2 receptors decreased the effects of afobazole on microglia. In addition to inhibiting microglial cell migration, activation of receptors by afobazole decreased intracellular calcium elevation produced by focal application of ATP and UTP in isolated microglial cells. Furthermore, afobazole blocked membrane currents elicited by rapid application of ATP in microglial cells. Taken together, our data indicate that afobazole inhibits microglial response to P2Y and P2X purinergic receptor activation by functioning as a pan-selective -receptor agonist. In addition to modulating response to purinergic receptor activation, the effects of afobazole on microglial survival during in vitro ischemia were assessed. Application of afobazole during in vitro ischemia decreased microglial cell death during the ischemic episode and after a 24-h recovery period. Moreover, when afobazole was only applied after the ischemic episode, a significant enhancement in cell survival was still observed. Thus, afobazole acts via receptors to decrease microglial response to ATP and provides cytoprotection during and after ischemia.

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Section: Resultsmentioning

confidence: 99%

Afobazole Modulates Microglial Function via Activation of Both σ-1 and σ-2 Receptors

Cuevas¹,

Rodríguez²,

Behensky³

et al. 2011

J Pharmacol Exp Ther

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“…However, it is unclear whether afobazole is acting directly on caspase-3 or through some upstream signaling molecule. Another putative afobazole target for neuroprotection is receptors, which have been postulated as an effector for this drug (Seredenin et al, 2009). Afobazole has a pharmacophore structure similar to that of the -1-receptor agonist (ϩ)-pentazocine.…”

Section: Discussionmentioning

confidence: 99%

“…Afobazole has a pharmacophore structure similar to that of the -1-receptor agonist (ϩ)-pentazocine. Binding studies showed that afobazole displaces (ϩ)-pentazocine in Jurkat cells with an IC 50 of 7 M (Seredenin et al, 2009). Application of afobazole onto HT-22 cells results in translocation of -1 receptors from the cell body to axons, suggesting possible activation of the receptors by afobazole (Seredenin et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Afobazole was found to displace [ 3 H](ϩ)-pentazocine in a Jurkat cells assay with an IC 50 of approximately 10 M (Seredenin et al, 2009). Moreover, afobazole was found to promote mobilization of -1 receptors to the plasma membrane in HT-22 cells, also suggesting an afobazole--1-receptor interaction (Seredenin et al, 2009). However, it has not been established whether afobazole functions as an agonist or an antagonist at -1 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…The chemical structure of afobazole shares the pharmacophore structure with the -1-receptor ligand, (ϩ)-pentazocine (Walker et al, 1990), which motivated a recent study on the interaction of afobazole with these receptors (Seredenin et al, 2009). Afobazole was found to displace [ 3 H](ϩ)-pentazocine in a Jurkat cells assay with an IC 50 of approximately 10 M (Seredenin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Afobazole Modulates Neuronal Response to Ischemia and Acidosis via Activation of σ-1 Receptors

Cuevas¹,

Behensky²,

Deng³

et al. 2011

J Pharmacol Exp Ther

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Afobazole is an anxiolytic medication that has been previously shown to be neuroprotective both in vitro and in vivo. However, the mechanism(s) by which afobazole can enhance neuronal survival remain poorly understood. Experiments were carried out to determine whether afobazole can decrease intracellular calcium overload associated with ischemia and acidosis and whether the effects of afobazole are mediated via interaction of the compound with receptors. Fluorometric Ca 2ϩ imaging was used to resolve how application of afobazole affects intracellular Ca 2ϩ handling in cortical neurons. Application of afobazole significantly depressed, in a concentration-dependent and reversible manner, the intracellular Ca 2ϩ overload resulting from in vitro ischemia and acidosis. The IC 50 for afobazole inhibition of ischemia-evoked intracellular Ca 2ϩ overload was considerably less than that for the inhibition of [Ca 2ϩ ] i increases induced by acidosis. However, afobazole maximally inhibited only 70% of the ischemia-evoked intracellular Ca 2ϩ overload but effectively abolished intracellular Ca 2ϩ increases produced by acidosis. The effects of afobazole on ischemia-and acidosis-induced intracellular Ca 2ϩ dysregulation were inhibited by preincubating the neurons in the irreversible, pan-selective -receptor antagonist, metaphit. Moreover, the effects of afobazole on intracellular Ca 2ϩ increases triggered by acidosis and ischemia were blocked by the selective -1-receptor antagonists, BD 1063 and BD 1047, respectively. Experiments examining the effects of afobazole on neuronal survival in response to ischemia showed that afobazole was neuroprotective. Taken together, these data suggest that afobazole regulates intracellular Ca 2ϩ overload during ischemia and acidosis via activation of -1 receptors. This mechanism is probably responsible for afobazole-mediated neuroprotection.

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