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Fusidic acid suppresses nitric oxide toxicity in pancreatic islet cells
V Burkart1, K Bellmann, B Hartmann
1Diabetes Research Institute, University of Düsseldorf, Germany.
Abstract:
Earlier preclinical and clinical trials indicate that fusidic acid, a triterpenoid compound originally described as an antimicrobial drug may protect islet beta cells from destruction in type I (insulin-dependent) diabetes mellitus. Since nitric oxide appears to be an important mediator of inflammatory islet cell death we analyzed whether fusidic acid interferes with nitric oxide production or action. We report here that fusidic acid dose-dependently inhibits lysis of isolated islet cells by activated macrophages, a process mediated by nitric oxide. In the presence of 100 microM fusidic acid macrophage-mediated islet cell lysis was reduced from 52.5 to 1.7% (P < 0.001). Fusidic acid only slightly affected macrophage function and did not inhibit the release of nitric oxide. We therefore tested whether fusidic acid suppresses nitric oxide toxicity in target cells. Isolated islet cells were exposed to the nitric oxide donor nitroprusside which led to DNA strand breaks and plasma membrane lysis. DNA strand breaks were reduced from 54.6 to 34.9% (P < 0.001) in the presence of 100 microM fusidic acid and cell lysis was reduced from 60.1 to 27.5% with 100 microM (P < 0.001). In the presence of 500 microM fusidic acid DNA strand breaks and cell lysis were reduced further to 27.1 and 10.7%, respectively (P < 0.001). No protection by fusidic acid was observed when cells were exposed to oxygen radicals or the alkylating beta cell toxin streptozotocin. The suppression of nitric oxide toxicity by fusidic acid was not due to its known inhibitory action on protein biosynthesis and thus represents a hitherto unknown activity of this drug.
Insights
Fusidic acid, an antimicrobial drug, protects islet beta cells from nitric oxide-mediated destruction in type 1 diabetes. This novel finding suggests a new therapeutic role for fusidic acid in managing diabetes by reducing inflammatory cell death.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Type 1 diabetes involves islet beta cell destruction.
- Nitric oxide (NO) is implicated in inflammatory islet cell death.
- Fusidic acid, an antimicrobial, may offer protective effects for beta cells.
Purpose of the Study:
- To investigate if fusidic acid interferes with nitric oxide production or action.
- To determine fusidic acid's effect on macrophage-mediated islet cell lysis.
- To assess fusidic acid's ability to suppress nitric oxide toxicity in islet cells.
Main Methods:
- Assessed fusidic acid's effect on isolated islet cell lysis induced by activated macrophages.
- Measured nitric oxide release from macrophages in the presence of fusidic acid.
- Exposed islet cells to a nitric oxide donor (nitroprusside) with and without fusidic acid.
- Evaluated DNA strand breaks and plasma membrane lysis as indicators of cell damage.
- Tested fusidic acid's protective effects against oxygen radicals and streptozotocin.
Main Results:
- Fusidic acid dose-dependently inhibited macrophage-mediated islet cell lysis.
- Fusidic acid did not inhibit nitric oxide release or significantly affect macrophage function.
- Fusidic acid reduced nitric oxide-induced DNA strand breaks and cell lysis in a dose-dependent manner.
- Fusidic acid did not protect cells from oxygen radicals or streptozotocin.
- The protective effect was independent of fusidic acid's known inhibition of protein biosynthesis.
Conclusions:
- Fusidic acid suppresses nitric oxide-mediated toxicity to islet beta cells.
- This represents a novel, previously unrecognized activity of fusidic acid.
- Fusidic acid shows potential as a therapeutic agent for type 1 diabetes by protecting beta cells from inflammatory damage.