Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway

Jan 7, 2026Acta pharmacologica Sinica

A Sigma-1 receptor enhancer helps brain cell survival and improves thinking problems in Alzheimer's mice through the sigma-1 receptor and ERK pathway

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Abstract

SOMCL-668, a novel sigma-1 receptor modulator, shows neuroprotective effects in Alzheimer's disease models.

SOMCL-668 protects PC12 cells from Aβ-induced oxidative stress and neuronal cell death.
The neuroprotective effect of SOMCL-668 is confirmed in SH-SY5Y cells and primary cortical neurons.
Activation of the sigma-1 receptor is essential for SOMCL-668's protective effects, as shown by CRISPR-Cas9 knockout studies.
In 3xTg-AD mice, SOMCL-668 improves learning and memory, reduces oxidative stress, and decreases Aβ deposition and tau protein phosphorylation.
Pharmacological inhibition of ERK attenuates the protective effects of SOMCL-668, suggesting involvement of the ERK/CREB signaling pathway.

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The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.

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Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway

Abstract

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