A second act for spironolactone: cognitive benefits in renal dysfunction - a critical review

Renal dysfunction or Chronic kidney disease (CKD) are increasingly associated with cognitive deficit and memory impairment, suggesting a crucial kidney-brain axis. This review examines spironolactone's emerging role as a neuroprotective agent in the context of renal dysfunction-induced cognitive impairment. As a selective mineralocorticoid receptor (MR) antagonist, spironolactone demonstrates multifaceted protective mechanisms beyond its well established renoprotective effects. Evidences also suggests that spironolactone attenuates neuroinflammation, mitigates oxidative stress in brain, preserve blood-brain barrier (BBB) integrity and regulates hormonal imbalances associated with renal dysfunction. This review focuses on the reported beneficial effects of spironolactone in various neurodegenerative diseases (NDDs). These mechanisms collectively protect against the neurodegeneration in memory impairment induced by renal dysfunction. The dual action of spironolactone on both renal and cerebral tissues presents a novel therapeutic advantage in addressing this complex pathophysiology. This study elucidates multiple beneficial mechanisms by which spironolactone addresses cognitive impairment associated with renal dysfunction. Spironolactone enhances BBB protection and restores BBB integrity which is often compromised with renal dysfunction. It promotes neuroplasticity (allowing for improved neural adaptation and cognitive function), additionally mediates cerebral blood flow (CBF) ensuring adequate oxygen and nutrient delivery to brain. Spironolactone's anti-inflammatory effects by inhibiting the nuclear factor-kappa B (NF-κB) pathway and modulation of neuregulin1 (NRG1)/v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4 (ERBB4) signaling effectively reduce neuroinflammation that contributes to memory impairment. It also mitigates oxidative stress by targeting NADPH-oxidase (NOX), a major source of reactive oxygen species (ROS) in the central nervous system (CNS). Spironolactone also maintains hormonal balance, particularly regarding aldosterone levels, which become dysregulated in renal dysfunction and negatively impact brain function. These insights provide new possibilities for developing targeted therapies against renal dysfunction-induced memory impairment.