Intranasal deferiprone delivery increases brain exposure and ameliorates abnormal open-field behavior in a mouse model of brain iron dysregulation

Introduction Although brain iron dysregulation has been implicated in neurological and neuropsychiatric disorders, its potential as a therapeutic target remains unclear. Deferiprone (DFP), an oral lipophilic iron chelator approved for systemic iron overload, has been explored for central nervous system (CNS) disorders, but its use has been limited by systemic toxicity and suboptimal brain distribution. In this study, we evaluated intranasal (IN) delivery of DFP as an alternative strategy to modulate impaired neurobehavior in a mouse model of brain iron accumulation. Methods Wild‐type and H67D mice (male, n = 6–10 per group) received IN or oral DFP daily for 7 days, followed by open field testing and hematological assessment. To determine whether the behavioral effects and hematological tolerability of IN administration were associated with route‐dependent exposure, we evaluated pharmacokinetics and compared tissue distribution of DFP following IN and oral administration. Results In contrast to high-dose oral treatment, IN administration of DFP produced behavioral effects at 20 mg/kg without detectable hematological changes, whereas high-dose oral DFP (100 mg/kg) reduced circulating leukocyte and neutrophil counts without producing comparable behavioral effects. Pharmacokinetic analysis revealed increased drug distribution in the olfactory bulb and distinct brain-to-plasma distribution patterns after IN administration relative to oral dosing. Conclusion Collectively, our findings demonstrate that intranasal delivery alters regional CNS exposure to DFP and improves open-field behavior associated with brain iron dysregulation.