The Effects of Deferoxamine, an Iron Chelator, on Traumatic Brain Injury Sequelae

This study investigated the effects of deferoxamine (DFO), an iron chelator, on outcomes following traumatic brain injury (TBI). DFO has shown promise in treating various neurodegenerative conditions and stroke-induced injury due to its multiple mechanisms of action, including reduction of reactive oxygen species, inhibition of ferroptosis, and activation of the transcription factor HIF-1. We hypothesized that, because HIF-1 is known to promote the formation of new blood vessels and vascular remodeling, HIF-1 activation via DFO-induced HIF-1⍺ stabilization may improve outcomes after TBI in part due to enhanced NVU repair, leading to reduced blood-brain barrier permeability and therefore decreased neuroinflammation.

Male and female mice were subjected to controlled cortical impact to model TBI, with a sham procedure as control. DFO or saline was administered daily for two weeks post-injury. Behavioral tests assessed locomotor function, balance, neurological impairment, and short-term recognition memory. At 14 days post-injury, cortical HIF-1α levels and blood-brain barrier permeability were evaluated via Western blot and a novel sodium fluorescein-based assay.

Results showed no statistically significant differences in locomotor function, balance, cortical HIF-1α levels, or blood-brain barrier permeability associated with DFO treatment in TBI mice. However, significant improvements in TBI-induced neurological impairment were observed in both sexes treated with DFO. Additionally, DFO-treated females with TBI showed improved short-term recognition memory, a trend not observed in males.

These findings suggest that DFO may have beneficial effects on certain aspects of recovery after TBI, particularly in reducing neurological impairment. However, the mechanism of action does not appear to involve decreased neuroinflammation through HIF-1-mediated reductions in blood-brain barrier permeability.

Future research will focus on increasing sample size and DFO dose to validate the sexual dimorphic trend observed in short-term recognition memory, extending treatment duration to evaluate long-term effects, and adding other behavioral assays to gain a more robust understanding of the drug’s effects. Comparing HIF-1 knockout and wild-type mice will help confirm if the observed improvements are truly HIF-1-independent. Investigation into DFO's effects on oxidative stress and ferroptosis after TBI is also planned.