Candesartan protects against d-galactose induced - Neurotoxicity and memory deficit via modulation of autophagy and oxidative stress

Toxicol Appl Pharmacol. 2022 Jan 15:435:115827. doi: 10.1016/j.taap.2021.115827. Epub 2021 Dec 11.

Abstract

Purpose: d-galactose induces neuroinflammation and memory deficit via oxidative stress. Candesartan is an angiotensin II-receptor blocker and has proved neuroprotective properties. This study aimed to investigate the neuroprotective effect of candesartan against d-galactose induced neuroinflammation and memory deficit via autophagy.

Methods: Twenty-eight male Wistar rats aged 3 months were divided into four equal groups: control (vehicle), d-gal (100 mg/kg d-galactose), cand (1 mg/kg candesartan), and cand+d-gal (100 mg/kg d-galactose & 1 mg/kg candesartan). All treatments were given orally and daily for 4 weeks. Assessment of memory was done using Morris water maze (MWM) test. Brain tissue was assessed for malondialdehyde (MDA), total thiol, catalase activity, glial fibrillary acidic protein (GFAP) and gene expression of TNF-α, GDNF-1 as well as autophagy genes (Beclin 1 and ATG 5).

Results: Prophylactic treatment of candesartan in d-galactose-treated rats significantly (p < 0.001) reduced oxidative stress via reduction of MDA as well as elevation of catalase activity and total thiol levels. Additionally, candesartan prophylactic treatment significantly increased gene expression of GDNF-1 and decreased gene expression of TNF-α. Furthermore, candesartan significantly increased the expression of autophagy related gene (Beclin 1 and ATG 5) in cand+d-gal treated rats. These results were supported by the histopathological findings which showed that candesartan prevented the neuronal injury in the cerebral cortex and hippocampus and decreased GFAP positive cells of the d-galactose-treated rats. Moreover, MWM test showed that candesartan significantly improved memory deficit in cand+d-gal treated rats.

Conclusion: Candesartan prevents d-galactose-induced neurotoxicity and memory deficit via activating autophagy and decreasing oxidative stress. Therefore, candesartan was a good candidate for age-related neurodegenerative disorders and memory deficit.

Keywords: Autophagy; Beclin 1; Candesartan; GDNF-1; Neurotoxicity; d-galactose.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Autophagy-Related Protein 5 / metabolism
  • Beclin-1 / metabolism
  • Benzimidazoles / therapeutic use*
  • Biphenyl Compounds / therapeutic use*
  • Galactose / antagonists & inhibitors
  • Galactose / toxicity*
  • Gene Expression / drug effects
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / chemically induced*
  • Memory Disorders / prevention & control*
  • Memory Disorders / psychology
  • Nervous System Diseases / chemically induced*
  • Nervous System Diseases / prevention & control*
  • Nervous System Diseases / psychology
  • Neuroprotective Agents / therapeutic use*
  • Oxidative Stress / drug effects*
  • Oxidative Stress / genetics
  • Rats
  • Rats, Wistar
  • Tetrazoles / therapeutic use*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Atg5 protein, rat
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, rat
  • Benzimidazoles
  • Biphenyl Compounds
  • GFAP protein, rat
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein
  • Neuroprotective Agents
  • Tetrazoles
  • Tumor Necrosis Factor-alpha
  • candesartan
  • Galactose