Potential regulation of kynurenine pathway metabolism by the galantamine-memantine combination in rheumatologic diseases: A hypothesis-driven review.

Recent studies have highlighted the pivotal role of the kynurenine pathway (KP) in systemic inflammatory disorders. Although KP modulation has been explored in diseases such as dementia and schizophrenia, its therapeutic potential in rheumatologic diseases remains largely unexplored. The objective of this article is to explore the potential role of the galantamine-memantine combination, with or without N-acetylcysteine (NAC), in regulating KP metabolism and its possible relevance to the pathophysiology of rheumatologic diseases. This article proposes a novel therapeutic strategy involving a combination of galantamine, a modulator of nicotinic receptor, and memantine, a N-methyl-D-aspartate receptor antagonist, with or without NAC, to target KP dysfunction in rheumatologic diseases. Galantamine and memantine may exert synergistic neuroimmune effects by reducing the production of neurotoxic KP metabolites, such as quinolinic acid, while promoting protective branches of the pathway. NAC, through its antioxidant properties, may further support this approach by mitigating oxidative stress and restoring immune balance. This combined therapy seeks to address key mechanisms of inflammatory rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, osteoarthritis, and psoriatic arthritis. This multifaceted approach may represent a potential direction for the treatment of rheumatologic diseases by integrating metabolic, neuroimmune, and antioxidant pathways. If future studies support the proposed mechanistic interactions, galantamine-memantine combination could potentially be explored as an adjunctive strategy alongside existing therapies. However, its clinical impact on treatment requirements or health care costs remains unknown and requires investigation in well designed randomized controlled trials. SIGNIFICANCE STATEMENT: A growing body of evidence in rheumatologic diseases implicates the kynurenine pathway (KP) metabolism. The galantamine-memantine combination, with or without N-acetylcysteine, through its regulatory action in KP could potentially be explored as an adjunctive strategy alongside existing therapies. Future randomized controlled trials are essential to establish efficacy, safety, and optimal patient selection.