Involvement of H2 S, NO and BDNF-TrkB signalling pathway in the protective effects of simvastatin against pentylenetetrazole-induced kindling and cognitive impairments in mice.

Abstract

Cognitive dysfunction was observed in pentylenetetrazole (PTZ)-kindled mice. The potential effectiveness of simvastatin (SIM) on PTZ-induced kindling and cognitive impairments in mice was evaluated. The influence of SIM on hydrogen sulphide (H2 S), nitric oxide (NO), reactive aldehydes and brain-derived neurotrophic factor/tyrosine receptor kinase B (BDNF-TrkB) signalling was also investigated. Kindling and cognitive impairments in mice were induced by 12 ip injections of PTZ (35 mg/kg) once every alternate day. The levels of reactive aldehydes and nitrite were increased while H2 S was decreased in PTZ-treated mice. These results were accompanied by a reduction in the gene expression of aldehyde dehydrogenase 2, cystathionine β-synthase, BDNF and TrkB. In PTZ-kindled mice, a rise in brain inducible nitric oxide synthase protein expression associated with histopathological changes was observed. SIM administration (1, 5 and 10 mg/kg, daily orally) along with alternate day of PTZ (35 mg/kg) resulted in a decrease in PTZ-induced kindling with a dose-dependent improvement in cognitive function. SIM (10 mg/kg) prevented, to variable extent, the disturbances associated with PTZ-kindled mice with cortical, cerebellar and hippocampal structural improvement. These results suggested that SIM triggers multiple mechanisms that improve cognitive function in PTZ-kindled mice through modulation of oxidative stress, H2 S, NO and BDNF-TrkB signalling pathway.

• Authors: Marwa A Ahmed, Esam O Kamel
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 127 Issue 6 Pg. 461-476 (Dec 2020) ISSN: 1742-7843 [Electronic] England
• PMID: 32562563 (Publication Type: Journal Article)
• Copyright: © 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.

Chemical References

• Bdnf protein, mouse
• Brain-Derived Neurotrophic Factor
• Membrane Glycoproteins
• Nitric Oxide
• Simvastatin
• Ntrk2 protein, mouse
• Protein-Tyrosine Kinases
• Pentylenetetrazole
• Hydrogen Sulfide

Topics

• Animals
• Avoidance Learning (drug effects)
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism, physiopathology)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cognition (drug effects)
• Cognitive Dysfunction (metabolism, physiopathology, prevention & control, psychology)
• Disease Models, Animal
• Hydrogen Sulfide (metabolism)
• Kindling, Neurologic (drug effects)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Morris Water Maze Test (drug effects)
• Nitric Oxide (metabolism)
• Pentylenetetrazole
• Protein-Tyrosine Kinases (metabolism)
• Signal Transduction
• Simvastatin (pharmacology)