Details

Autor(en) / Beteiligte

• Behensky, Adam A
• Yasny, Ilya E
• Shuster, Alexander M
• Seredenin, Sergei B
• Petrov, Andrey V
• Cuevas, Javier

Titel

Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25-35

Ist Teil von

• The Journal of pharmacology and experimental therapeutics, 2013-11, Vol.347 (2), p.458

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Aβ, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Aβ25-35-evoked migration were concentration dependent and consistent with σ-receptor activation. When afobazole was coapplied with either BD-1047 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide] or rimcazole, which are σ-1- and σ-2-selective antagonists, respectively, the inhibition of Aβ25-35-induced migration by afobazole was reduced. Prolonged exposure of microglia to Aβ25-35 resulted in glial cell death that was associated with increased expression of the proapoptotic protein Bax and the death protease caspase-3. Coapplication of afobazole with Aβ25-35 decreased the number of cells expressing both Bax and caspase-3 and resulted in a concomitant enhancement in cell survival. Although afobazole inhibited activation of microglia cells by Aβ25-35, it preserved normal functional responses in these cells after exposure to the amyloid peptide. Intracellular calcium increases induced by ATP were depressed in microglia after 24-hour exposure to Aβ25-35. However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of σ-1 and σ-2 receptors by afobazole prevents Aβ25-35 activation of microglia and inhibits Aβ25-35-associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics.