Targeting the sigma-1 receptor chaperone in the treatment of perinatal brain injury

Glutamate-induced excitotoxicity via the N-methyl-d-aspartate (NMDA) receptor is an important factor in the pathogenesis of perinatal brain injury. The sigma-1 receptor on the endoplasmic reticulum (ER) has been known to affect the function of the NMDA receptor. 4-Phenyl-1-(4-phenylbutyl)piperidine (PPBP) has been investigated as a sigma-1 receptor agonist for several decades. An article using PPBP in a model of preterm brain injury was published in Experimental Neurology. The authors reported that PPBP protected against glutamate-induced excitotoxicity in primary hippocampal neurons. Furthermore, the systemic administration of PPBP significantly reduced microglial activation and lesion size in cortical gray and white matter after the excitotoxic insult in neonatal mice. This study suggests that sigma-1 receptor agonists could be potential preventive and therapeutic drugs for perinatal brain injury, although a pharmacological experiment using a sigma-1 receptor antagonist was not performed. This commentary aims to highlights the key findings of this article in a broader context, emphasizing the future potential therapeutic applications in patients with perinatal brain injury.