Doxepin Attenuates Cognitive and Anxiety-like Behavioral Deficits Induced by Acute Kidney Injury in Rats.

Abstract

Introduction: Acute kidney injury (AKI) is a systemic disorder with consequences extending beyond the kidney, including central nervous system dysfunction. Clinical and experimental evidence indicates that AKI is associated with cognitive impairment and neuropsychiatric disturbances. However, effective strategies to prevent or attenuate AKI-associated brain dysfunction are lacking. Doxepin, a tricyclic antidepressant, exhibits neuroprotective properties that may counteract key mechanisms implicated in AKI-induced neural injury.

Methods: In this study, acute renal failure (ARF) was used as an experimental model of AKI. ARF was induced in male Wistar rats through glycerol injection. Animals were allocated into four experimental groups: Control, doxepin (DOX), ARF, or ARF-DOX. Doxepin was given orally at a dose of 5 mg/kg once daily over a 12-day period. Renal function was assessed using serum and urinary urea measurements. Anxiety-related behavior was assessed using the open field test and the elevated plus maze, whereas spatial learning and memory were evaluated with the radial arm water maze.

Results: Glycerol-induced ARF resulted in significant alterations in urinary parameters, including reduced urinary urea concentration and increased urine output and flow rate, while serum urea levels did not differ significantly among groups. ARF did not impair spatial learning acquisition but significantly disrupted short- and long-term memory retention. In addition, ARF induced specific anxiety-like behavioral alterations, including increased freezing behavior, reduced rearing activity, and decreased open-arm entries in anxiogenic environments. Doxepin treatment significantly attenuated memory impairments and partially normalized anxiety-related behaviors, without improving biochemical markers of renal dysfunction.

Discussion: These findings demonstrate that AKI induces selective cognitive and anxiety-like behavioral deficits and support the existence of a kidney-brain axis. Doxepin attenuated AKI-associated neurobehavioral impairments.

Conclusion: This study supports the potential repurposing of doxepin, an established clinically used and brain-penetrant drug, as a therapeutic strategy for attenuating AKI-associated neurobehavioral dysfunction.