Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-β_25–35

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-b (Ab) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the panselective s-receptor agonist afobazole can modulate microglial response to the cytotoxic Ab fragment, Ab [25][26][27][28][29][30][31][32][33][34][35] . Treatment with afobazole decreased microglial activation in response to Ab, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Ab 25-35 -evoked migration were concentration dependent and consistent with s-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 s-1-and s-2-selective antagonists, respectively, the inhibition of Ab 25-35 -induced migration by afobazole was reduced. Prolonged exposure of microglia to Ab 25-35 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 Ab 25-35 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 Ab [25][26][27][28][29][30][31][32][33][34][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 Ab [25][26][27][28][29][30][31][32][33][34][35] . However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of s-1 and s-2 receptors by afobazole prevents Ab [25][26][27][28][29][30][31][32][33][34][35] activation of microglia and inhibits Ab 25-35 -associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics.

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

“…Both S1R and BDNF were present in BV-2 microglial cells, yet treating these cells with an S1R agonist did not facilitate BDNF secretion. Although activated microglia (Nakajima et al, 2001; Sun et al, 2014), including a murine N9 microglial cell line (Gomes et al, 2013), are capable of secreting BDNF, our finding is in agreement with numerous studies indicating that the S1R is present in microglia and can modulate injury or toxicant-induced microgliosis by various mechanisms not involving BDNF (Behensky et al, 2013; Cuevas et al, 2011; Dong et al, 2015; Gekker et al, 2006; Hall et al, 2009; Mancuso et al, 2012; Moritz et al, 2015; Robson et al, 2013; Wegleiter et al, 2014; Wu et al, 2015; Zhao et al, 2014). Alternatively, the BV-2 cell line may lack the necessary machinery for investigating S1R-BDNF interactions in microglia or the microglia may need to be activated in order to study the effect.…”

Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

“…However, the differences in the effects of afobazole and M-11 indicate that in case of afobazole, other drug targets also contribute to the protective effect. This statement corresponds to a series of papers proving the involvement of σ 1 receptors, one of the main targets of afobazole, in its protective action when simulating the various pathological conditions in vitro [8,9,11]. The work was supported by the Russian Foundation for Basic Research (State Contract No.13-04-01014).…”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…Sigma ligands also improved microglial cell survival during and at least 24 h after ischemia [100], as well as after toxic exposure to amyloid beta in primary microglia cultures [102]. These data suggest that sigma receptors may modify microglial reactivity to strengthen the reparative microglia phenotype (M2) while attenuating the inflammatory response (M1).…”