Figures & data
Figure 1. Metformin and methotrexate may interact at the cellular level via AMP-activated protein kinase. Simplified schemeCitation43,Citation49 of the proposed “anti-inflammatory” activity of methotrexate. Increase of AICAR (structure shown in the inset) by inhibition of the bifunctional enzyme AICAR transformylase (AICART or ATIC)Citation50 is suggested to inhibit AMP and adenosine deaminase, leading to increased release of adenosine. Although it is generally postulated that the inhibition of AICART is by direct action of methotrexate polyglutamates, there are alternative explanations. These are based on the reversibility of the reaction (indicated by the double-headed arrow) and that AICART has rather low affinity for the polyglutamates. As an exception to all other reactions in mammalian one-carbon metabolismCitation51 10-formyl-7, 8-dihydrofolate and dihydrofolate can be substrate and product, respectively.Citation52 Increase of the product by blockade of the dihydrofolate reductase will slow the reaction and lead to increase in AICAR. FPGS, Folyl-Poly-Glutamyl- Synthase. Green arrows indicate activation; red lines with masthead indicate inhibition, broken line: disputed activity.
Table 1. Metformin and AICar exhibit anti-inflammatory and immunosuppressive activity in experimental systems
Table 2. Molecular mechanisms and targets for metformin and methotrexate
Figure 2. Simplified scheme how metformin and AICAr act as anti-inflammatory or immunosuppressive agents. Green arrows indicate activation or stimulation; Red lines with masthead indicate inhibition. Metformin may not only stimulate AMPK but block excessive reactive oxygen species (ROS) formation by mitochondria, which can activate the Nuclear Factor (NF)–ΚB pathway (not shown). For details on the role of AMPK in macrophages, see ref. Citation115. Molecular detailed pathways are found in ref. Citation120.
