Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2 S-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, H2 S, 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 H2 S, 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 H2 S, decrease Aβ, activate Nrf2-dependent antioxidant system, and decrease neuroinflammation.

• Authors: Li Chen, Rui Shi, Xia She, Chaochao Gu, Li Chong, Lina Zhang, Rui Li
• Journal: Fundamental & clinical pharmacology (Fundam Clin Pharmacol) Vol. 34 Issue 6 Pg. 697-707 (Dec 2020) ISSN: 1472-8206 [Electronic] England
• PMID: 32484999 (Publication Type: Journal Article)
• Copyright: © 2020 Société Française de Pharmacologie et de Thérapeutique.

Chemical References

• Amyloid beta-Peptides
• Brain-Derived Neurotrophic Factor
• Mineralocorticoid Receptor Antagonists
• NF-E2-Related Factor 2
• Neuroprotective Agents

Topics

• Alzheimer Disease (chemically induced, metabolism)
• Amyloid beta-Peptides
• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Cognition (drug effects)
• Disease Models, Animal
• Female
• Injections
• Male
• Maze Learning (drug effects)
• Mice
• Mineralocorticoid Receptor Antagonists (administration & dosage, pharmacology)
• NF-E2-Related Factor 2 (metabolism)
• Neuroprotective Agents (administration & dosage, pharmacology)
• Signal Transduction (drug effects)