Increased sensivity to infection due to memantine-induced blocking of inlammatory cell trafficking

Abstract

Memantine is a selective N-methyl-d-aspartate receptor antagonist, used clinically for treating Alzheimer’s disease. The proposed mechanism of action is the blocking of inflammatory cells infiltration into the brain and spinal cord. Previously, we uncovered the potential of memantine to ameliorate symptoms of experimental autoimmune encephalomyelitis (EAE) in old rats [previously published in: Bufan B et al (2024), Biomedicines 12 (4):717]. Here, we have treated female dark agouti rats (3 and 22 months old) with memantine (60 mg/kg body weight) for 7 days (1st–7th day post-immunization for EAE). On the 7th day, we assayed peritoneal and blood leukocytes for their phenotype and functionality. Memantine treatment reduced the expression of the surface major histocompatibility complex class II (MHCII) on peritoneal macrophages. Peritoneal macrophages were weakly responsive to in vitro LPS stimulation. Macrophages from old rats produced more nitric oxide (NO) ex vivo compared to macrophages from young rats. Cellularity of peritoneal cavity was inversely correlated with NO production, however memantine treatment seemed to reverse that correlation in old rats. Peritoneal cells from memantine-treated rats responded differently to phorbol 12-myristate 13-acetate (PMA) – there was an increased dihidrorhodamine fluorescence in all leucokytes, which was abrogated with memantine treatment, and in the old rat group there was a stronger PMA stimulation but reduced inhibitory effect of memantine. Among blood lymphocytes, there was a decreased expression of CD49d (CD43+CD62L+CD49d+), as well as an increased percentage of CD62L+ cells. Finally, while our results show a more pronounced effect of memantine in young rats, we have noticed that old rats under memantine treatment showed signs of nonEAE distress (rough fur, lethargy, respiratory issues). These results show the fast effect of memantine on a systemic level, as well as the potential downsides of its mechanism of action. *The authors marked with an asterisk equally contributed to the work