Deferiprone attenuates neuropathology and improves outcome following
traumatic brain injury
Abstract
Background and Purpose: Traumatic brain injury (TBI) remains a leading
cause of mortality and morbidity in young adults. The role of iron in
potentiating neurodegeneration following TBI has gained recent interest
since iron deposition has been detected in the injured brain in the
weeks to months post-TBI, in both the preclinical and clinical setting.
A failure in iron homeostasis can lead to oxidative stress, inflammation
and excitotoxicity; and whether this is a cause or consequence of the
long-term effects of TBI remains unknown. Experimental approach: We
investigated the role of iron, and the effect of therapeutic
intervention using a brain-permeable iron chelator, deferiprone, in a
controlled cortical impact mouse model of TBI. An extensive assessment
of cognitive, motor and anxiety/depressive outcome measures were
examined, and neuropathological and biochemical changes, over a 3-month
period post-TBI. Key Results: Lesion volume was significantly reduced at
3 months, which was preceded by a reduction in astrogliosis and a
preservation of neurons in the injured brain at 2 weeks and/or 1-month
post-TBI in mice receiving oral deferiprone. Deferiprone treatment
showed significant improvements in neurological severity scores and
locomotor/gait performance, and cognitive function, and attenuated
anxiety-like symptoms post-TBI. Deferiprone reduced iron levels,
oxidative stress and altered expression of neurotrophins in the injured
brain over this period. Conclusion and Implications: Our findings
support a detrimental role of iron in the injured brain and suggest that
deferiprone (or similar iron chelators) may be promising therapeutic
approaches to improve survival, functional outcomes and quality of life
following TBI.