Mitochondrial involvement in memory impairment induced by scopolamine in rats

Abstract

Objective: Scopolamine (SCO) administration to rats induces molecular features of AD and other dementias, including impaired cognition, increased oxidative stress, and imbalanced cholinergic transmission. Although mitochondrial dysfunction is involved in different types of dementias, its role in cognitive impairment induced by SCO has not been well elucidated. The aim of this work was to evaluate the in vivo effect of SCO on different brain mitochondrial parameters in rats to explore its neurotoxic mechanisms of action.

Methods: Saline (Control) or SCO (1 mg/kg) was administered intraperitoneally 30 min prior to neurobehavioral and biochemical evaluations. Novel object recognition and Y-maze paradigms were used to evaluate the impact on memory, while redox profiles in different brain regions and the acetylcholinesterase (AChE) activity of the whole brain were assessed to elucidate the amnesic mechanism of SCO. Finally, the effects of SCO on brain mitochondria were evaluated both ex vivo and in vitro, the latter to determine whether SCO could directly interfere with mitochondrial function.

Results: SCO administration induced memory deficit, increased oxidative stress, and increased AChE activities in the hippocampus and prefrontal cortex. Isolated brain mitochondria from rats administered with SCO were more vulnerable to mitochondrial swelling, membrane potential dissipation, H₂O₂ generation and calcium efflux, all likely resulting from oxidative damage. The in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly.

Conclusion: In conclusion, the present results indicate that SCO induced cognitive dysfunction and oxidative stress may involve brain mitochondrial impairment, an important target for new neuroprotective compounds against AD and other dementias.

Keywords:

• Scopolamine
• dementia
• Alzheimer’s disease
• oxidative stress
• mitochondrial dysfunction

Abbreviations:

• Ach: acetylcholine
• AChE: acetylcholinesterase
• AD: Alzheimer’s disease
• Alm: alamethicin
• ATCh: acetylthiocholine
• Ca²⁺: calcium
• CAT: catalase
• CCCP: carbonyl cyanide m-chlorophenyl hydrazone
• CNS: central nervous system
• DNA: deoxyribonucleic acid
• DTNB: 5,5′-dithiobis(2-nitrobenzoic acid)
• EDTA: ethylenediamine tetraacetic acid
• EGTA: ethylene glycol tetraacetic acid
• ERK: extracellular signal-regulated kinase
• FoxO3a: forkhead box subfamily O3a
• GSH: reduced glutathione
• H₂O₂: hydrogen peroxide
• HEPES: (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)
• HO: hippocampus
• KCl: potassium chloride
• KOH: potassium hydroxide
• MDA: malondialdehyde
• NOR: novel object recognition
• PC: prefrontal cortex
• PGC-1α: peroxisome proliferator-activated receptor γ co-activator 1α
• Pi: inorganic phosphate
• PI: phosphoinositide
• ROS: reactive oxygen species
• S.E.M.: standard errors of the mean
• SCO: scopolamine
• SOD: superoxide dismutase
• TBOOH: t-butyl hydroperoxide
• Ym: Y-maze