Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-β25–35

@article{Behensky2013StimulationOS,
  title={Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-$\beta$25–35},
  author={Adam A Behensky and Ilya E. Yasny and A. M. Shuster and Sergei B Seredenin and Andrey V. Petrov and Javier Cuevas},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2013},
  volume={347},
  pages={458 - 467}
}
  • A. Behensky, I. Yasny, J. Cuevas
  • Published 1 November 2013
  • Biology, Chemistry
  • The Journal of Pharmacology and Experimental Therapeutics
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-β (Aβ) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the pan-selective σ-receptor agonist afobazole can modulate microglial response to the cytotoxic Aβ fragment, Aβ25–35. Treatment with afobazole decreased microglial activation in response to A… 

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References

SHOWING 1-10 OF 65 REFERENCES
Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity
TLDR
The results suggest that σ1 receptor agonists might function as neuroprotectant agents in Alzheimer's disease.
Amyloid β-Induced Death in Neurons Involves Glial and Neuronal Hemichannels
TLDR
Aβ leads to a cascade of hemichannel activation in which microglia promote the release of glutamate and ATP through glial (microglia and astrocytes) hemich channels that induces neuronal death by triggering hemichannels in neurons.
Comparative study of microglia activation induced by amyloid‐beta and prion peptides: Role in neurodegeneration
TLDR
The data indicate that Aβ and PrP peptides caused microglia activation and differentially affected cytokine secretion.
Afobazole Modulates Neuronal Response to Ischemia and Acidosis via Activation of σ-1 Receptors
TLDR
Data suggest that afobazole regulates intracellular Ca2+ overload during ischemia and acidosis via activation of σ-1 receptors, which is probably responsible for afobzole-mediated neuroprotection.
Melatonin attenuates amyloid beta25–35-induced apoptosis in mouse microglial BV2 cells
Microglia Function in Alzheimer’s Disease
TLDR
Recent evidence supporting both the beneficial or detrimental performance of microglia in AD is discussed, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions is discussed.
Microglial Activation is Required for Aβ Clearance After Intracranial Injection of Lipopolysaccharide in APP Transgenic Mice
TLDR
Results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment, Nonetheless, microglial activation was necessary to remove Aβ in this model of neuroinflammation.
beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease.
TLDR
Three findings presented here support this mechanism, showing that beta-amyloid peptides activated the classical NADPH oxidase in rat primary culture of microglial cells and human phagocytes, and that neutrophils and monocytes of chronic granulomatous disease patients do not respond to beta- AML peptides with the stimulation of reactive oxygen intermediate production.
β-Amyloid Stimulation of Microglia and Monocytes Results in TNFα-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis
TLDR
A functional linkage between β-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains is demonstrated.
Sigma-1 Receptor Activation Prevents Intracellular Calcium Dysregulation in Cortical Neurons during in Vitro Ischemia
TLDR
The studies show that activation of sigma receptors can ameliorate [Ca2+]i dysregulation associated with ischemia in cortical neurons and identify one of the mechanisms by which these receptors may exert their neuroprotective properties.
...
...