Cutamesine attenuates hippocampal damage via sigma-1 receptor activation following oxygen-glucose deprivation in vitro

Cerebral ischemia is a leading cause of death and disability worldwide, due to neuronal energy failure, calcium overload, ER stress and inflammation. Sigma-1 receptor activation regulates calcium signaling between ER and mitochondria and reduces the activation of ER stress and inflammation pathways. In the present study, we investigated the neuroprotective effects of the sigma-1 receptor agonist cutamesine in rat organotypic, and acute hippocampal slices exposed to oxygen-glucose deprivation (OGD), two in vitro models of global ischemia. In organotypic hippocampal slices obtained from both sexes exposed to 30 min of OGD, we evaluated the neuroprotective effects of cutamesine by quantifying CA1 cell death via propidium iodide fluorescence. We also assessed mRNA and protein levels of key ER stress and inflammation markers via RT-qPCR and Western blot. In acute hippocampal slices, we evaluated the effects of cutamesine on recorded extracellular field excitatory postsynaptic potentials following OGD. Cutamesine exhibited neuroprotective effects at 10 μg/mL in organotypic hippocampal slices exposed to 30 min of OGD, and this effect was reduced by the sigma-1 receptor antagonist BD1047. Cutamesine reduced ER stress and inflammation pathways by decreasing GRP78, GRP94, p-p65, and MMP-9 protein levels and these effects were partially decreased by BD1047. Cutamesine also delayed the onset of anoxic depolarization latency on acute hippocampal slices obtained from male rats. These findings evidence the notion that the sigma-1 receptor may be a promising therapeutic target for ischemic injury.