In vitro ibuprofen has gene regulatory and anti-inflammatory properties in peripheral blood mononuclear cells of individuals with infection-provoked neurodevelopmental disorders.

Gene-environment interactions, leading to immune-brain cross-talk and neuroinflammation are increasingly recognised in neurodevelopmental disorders (NDDs), such as autistic regression and paediatric acute onset neuropsychiatric syndrome (PANS). Nonsteroidal anti-inflammatory drugs, including ibuprofen, provides relief to some neuropsychiatric symptoms, however, the therapeutic mechanisms are unclear. We describe the benefit of ibuprofen in 18 children (11 males, ages 5-20 years) with infection-provoked deteriorations compatible with PANS (16/18) or autistic regression (7/18), five met criteria for both. Ibuprofen was well tolerated and led to improved emotional control, obsessive-compulsive symptoms, and aggression during infection-related exacerbations or the chronic phase. Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) in two children and their respective age-, sex- matched controls, before and after 24 h of in vitro ibuprofen and/or paracetamol incubation. A total of 45,134 cells were included. At baseline in both cases, there was dysregulation of immune pathways (response to virus, cell killing) and downregulation of ribosomal and translational pathways. Ibuprofen reversed the pro-inflammatory state in both children with reversal of cell killing pathways (granzyme genes) in Case 1, and reversal of viral pathways (interferon genes) in Case 2. Ibuprofen also reversed translation pathways (ribosomal protein genes), and regulation of translation (including EIF genes). In vitro paracetamol produced similar but weaker effects than ibuprofen. Children with infection-provoked neurodevelopmental episodes have baseline transcriptional and immune dysregulation in peripheral immune cells. We show that ibuprofen has transcriptional and anti-inflammatory effects, and that scRNA-seq in vitro-based studies can inform disease-modifying therapies for individuals with NDDs.