Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2S-Nrf2 signaling

The present study explored the role and mechanisms of mineralocorticoid receptor antagonists in β-amyloid (Aβ)-induced cognitive impairment. A single intracerebroventricular injection of Aβ_1-42 was given to mice, and after 14 days of injection, memory was evaluated using the Morris water maze test. Spironolactone (25 and 50 mg/kg) and eplerenone (50 and 100 mg/kg) were administered for two days before and for 14 days after Aβ injection. Mineralocorticoid receptor blockers attenuated Aβ-induced cognitive impairment assessed in terms of decrease in day 4 escape latency time (ELT) in comparison to day 1 ELT (suggesting an increase in learning) along with an increase in time spent in target quadrant on day 5 (suggesting the retrieval of learned things). These drugs also increased the expression of BDNF, H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α in the frontal cortex and hippocampus. Co-administration of ANA-12, BDNF receptor antagonist (0.25 and 0.5 mg/kg) abolished cognitive improving functions of mineralocorticoid receptor blockers, attenuated H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α. It is concluded that spironolactone and eplerenone attenuate cognitive decline of Alzheimer's type, possibly through upregulation of BDNF levels in the frontal cortex and hippocampus, which may increase H₂S, decrease Aβ, activate Nrf2-dependent antioxidant system, and decrease neuroinflammation.