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

Abstract

The present study explored the role and mechanisms of mineralocorticoid receptor antagonists in β‐amyloid (Aβ)‐induced cognitive impairment. A single intracerebroventricular injection of Aβ1‐42 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.

Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

“…CART treatment improved spatial memory in the MWM task in rats infused with Aβ 1-42 into the hippocampus [93]. Mineralocorticoid receptor antagonists reduced memory impairment in the MWM task in mice with a brain infusion of Aβ 1-42 [94]. Mineralocorticoid receptor antagonists also activated the Nrf2-dependent antioxidant system.…”

Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α

“…Studies have shown the function of physiological and pathophysiological roles of H 2 S in the brain including traumatic brain injury 14 , 15 . Furthermore, other studies have pointed out the close interrelationship between H 2 S, neuroinflammation and Nrf2 16 , 17 .…”

Methionine restriction - Association with redox homeostasis and implications on aging and diseases

“…Furthermore, it is possible that the Nrf2 system is involved in cognitive decline in multiple diseases [ 222 ]. Nrf2 regulates, among others, the catalytic and modifying subunit of glutamate cysteine ligase (GCL) to increase GSH levels [ 223 ].…”