Background and Purpose: GRIN-related disorders are neurodevelopmental disorders caused by mutations in the N-methyl-D-aspartate receptor (NMDAR) subunit receptor GRIN genes. A large fraction of these mutations leads to gain of function (GoF) of the NMDAR. Patients present with a combination of symptoms that includes epilepsy, intellectual disability, behavioural and motor symptoms. Controlling seizures is a significant medical need in most patients with GRIN-related disorders. The aim of this study was to assess the therapeutic efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) mutation in homozygosity (Grin2aS/S mice). Experimental Approach: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction. Key Results: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Conclusion and Implications: Our data clearly indicates that radiprodil has the potential to control seizures in patients with GRIN2A GoF mutations, targeting the underlying pathophysiology of the disorder.

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and even death. Epidemiological data show that “diabesity”, the association of obesity and diabetes, is among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in diabesity argues for initial defects in defense mechanisms, most likely due to an elevated systemic metabolic inflammation (“metaflammation”). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of diabesity. Here we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.