ASPIRIN Cytomegalovirus (CMV) infections affect about 1% of pregnancies. For 20 % of CMV-infected infants, neurological consequences are severe, such as brain malformations, sensorimotor impairments, intellectual disability and seizures. Researchs have highlighted a strong link between immune response and the extent of CMV-damage. Here, the authors demonstrate in the rat that acetyl salicylic acid, or aspirin, during pregnancy dramatically improves survival rates and sensorimotor development, delays epileptic seizures and eliminates epileptiform activity . These benefits are associated with reduced CMV load and decreased Cox-1+ fetal microglia population. Yet another promising use for one of the world’s oldest medications?   (I. Bureau)

Scientific abstract: Background Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brainin utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection. Methods CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetyl-salicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1. Results Increased PGE2 levels and increased proportions of Cox-1+ and Cox-2+ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1 + fetal, but not neonatal,microglia, while leaving the proportions of Cox-2 + microglia unchanged. Maternal intake of ASA also improvedthe key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups. Conclusion Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.

The authors: Tarhini, Crespo-Quiles, Buhler, Pineau, Pallesi-Pocachard, Villain, Saha, Silvagnoli, Stamminger, Luche, Cardoso, Pais de Barros, Burnashev, Szepetowski & Bauer

published in Journal of Neuroinflammation, Nov 2024