Long-Term Exposure to Dexamethasone May Increase the Risk of Stroke by Sensitizing Cells to Ferroptosis

People with high blood pressure who are iron-supplementing may be at especially increased risk of stroke if exposed to dexamethasone

Dexamethasone, a synthetic corticosteroid, is widely used in medicine for its potent anti-inflammatory and immunosuppressive properties. It has been a staple in the treatment of conditions ranging from autoimmune diseases to severe allergies, and it plays a critical role in managing swelling and inflammation in cases such as brain injuries and spinal cord trauma.

However, despite its numerous benefits, dexamethasone is not without risks. Known side effects include osteoporosis, muscle weakness, peptic ulcers, and growth retardation in children. We’re going to focus on its potential effects on cardiovascular health, particularly its suspected role in increasing the risk of stroke.

Stroke, a leading cause of death and disability worldwide, occurs when the blood supply to part of the brain is interrupted or reduced, preventing brain tissue from getting the oxygen and nutrients it needs. When this happens, brain cells begin to die within minutes, causing irreversible damage. While common stroke risk factors such as hypertension, diabetes, and smoking are well understood, less attention has been given to how certain medications, like dexamethasone, may contribute to stroke risk through more subtle biological mechanisms.

Recent research has suggested that dexamethasone may increase the risk of stroke by sensitizing cells to ferroptosis, a regulated form of cell death driven by iron and characterized by the accumulation of lethal lipid peroxides. Ferroptosis has been linked to a range of diseases, including acute kidney injury, myocardial infarction, neurodegeneration, and stroke. The connection between dexamethasone and ferroptosis highlights how some prescribed medications might interact with complex biochemical pathways to bring about adverse events, including stroke.

Dexamethasone may heighten stroke risk by accelerating ferroptosis in vulnerable tissues, particularly in the brain. By examining the underlying mechanisms and clinical evidence, we aim to provide both healthcare professionals and informed lay readers with a deeper understanding of the potential risks associated with dexamethasone use, especially in populations already at risk for stroke.

Mechanisms of Action

von Mässenhausen et al., 2022 have reported a potential mechanism by which dexamethasone may increase susceptibility to stroke through its effects on ferroptosis. This section will explore the key findings and their implications.

Dexamethasone is also an anti-VEGF, used, for example, in intravitreal implants to stop retinal neovascularization and bleeding. One of the main concerns about anti-VEGF drugs, including dexamethasone is their systemic safety profile. Serious adverse events such as myocardial infarction, stroke, arteriothrombotic events, and serious hemorrhage have been described among others (Moja et al., 2014).

Glutathione Depletion

Dexamethasone has been shown to significantly decrease glutathione (GSH) levels in cells. GSH is a crucial antioxidant that protects cells from oxidative stress and ferroptosis. By depleting GSH, dexamethasone may leave cells more vulnerable to oxidative damage and ferroptotic cell death.

DPEP1 Upregulation

Studies have demonstrated that dexamethasone upregulates the expression of dipeptidase-1 (DPEP1) by activating the glucocorticoid receptor (GR). DPEP1 is an enzyme involved in GSH metabolism, and its increased activity may further contribute to GSH depletion.

Sensitization to Ferroptosis

Decreased GSH levels and increased DPEP1 activity sensitizes cells to ferroptosis. This effect was observed mainly in response to erastin, a compound that induces ferroptosis by inhibiting the cell's ability to import cystine, a precursor for GSH synthesis.

Tissue-Specific Effects: The Brain

While the studies primarily focused on kidney cells, the mechanisms identified could also apply to brain tissue (von Mässenhausen et al., 2022). Given that ferroptosis has been implicated in neuronal death during stroke, this sensitization effect could be particularly relevant in the context of cerebrovascular events.

Time and Dose-Dependence

The effects of dexamethasone on ferroptosis sensitivity were observed after 12 hours of treatment with 1 μM dexamethasone. This suggests that both the duration of treatment and the dose of dexamethasone may be important factors in determining its impact on stroke risk. Intravitreal implants that release the steroid over a long period of time should therefore be reviewed for the risk of stroke in certain patient populations.

The findings of von Mässenhausen et al., 2022 provide a plausible biological mechanism linking dexamethasone use to increased stroke risk. By sensitizing cells to ferroptosis, dexamethasone may exacerbate cellular damage during ischemic events, potentially leading to more severe outcomes in stroke.

Physicians treating diabetics for macular edema seeking alternatives to dexamethasone can find a profile comparison to Bevacizumab here.

Citations

Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;9:CD011230.

von Mässenhausen A, Zamora Gonzalez N, Maremonti F, Belavgeni A, Tonnus W, Meyer C, Beer K, Hannani MT, Lau A, Peitzsch M, Hoppenz P, Locke S, Chavakis T, Kramann R, Muruve DA, Hugo C, Bornstein SR, Linkermann A. Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion. Sci Adv. 2022 Feb 4;8(5):eabl8920. doi: 10.1126/sciadv.abl8920. Epub 2022 Feb 2. PMID: 35108055; PMCID: PMC8809683.