Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats

Vukšić, Antonija; Lovrić, Jasna; Konjevoda, Paško; Blažević, Nikola; Bilušić, Marinko; Bradamante, Vlasta

doi:10.2478/aiht-2019-70-3215

Cited by 5 publications

(18 citation statements)

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“…Additional significant specific organ insult caused by the statins could be the central nervous system since elevated oxidative stress biomarker MDA and the reduction of the antioxidant GSH content were also found in the whole brain of the treated mice in the present study. Albeit, these effects and the reported cholinesterase activity reduction [ 10 , 13 , 14 ], myopathy [ 3 , 5 ], and the current evidence considering the brain as a non-therapeutic (hypolipidemic) target for statins [ 28 ], could be related to neurobehavioral alterations reported in experimental animals [ 8 , 14 , 28 ]. Keeping these adverse effects in mind, especially those of the single statin doses, and in light of the possibility of statin intolerance [ 16 , 17 ] reported clinically, further in-depth exploration of an animal model for single-dose statin intolerance is warranted.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Al-Shalchi,

Mohammad

2024

Cureus

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Background and objective The hypolipidemic statins have been associated with various side effects, and in some cases, adverse reactions in humans and experimental animals, such as myotoxicity, neurobehavioral toxicity, as well as liver and kidney injuries. The purpose of the present study was to examine the possibility of the induction of oxidative stress in the brain and plasma of mice dosed with single or repetitive doses of three statins (atorvastatin, simvastatin, and rosuvastatin). Methods Male Swiss-origin mice were dosed orally with single doses of each of the three statins at 500 or 1000 mg/kg of body weight. Other groups of mice were dosed orally with repeated daily doses of each of the statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days. These doses of statins were chosen to not produce overt toxicity in mice within the time frame allocated for each experiment. Brain and plasma glutathione (GSH) and malondialdehyde (MDA) levels, as well as liver enzymes activities alanine transaminase (ALT) and aspartate transaminase (AST), were determined using commercial kits. Results Single-dose treatments of the mice with the statins at either 500 or 1000 mg/kg significantly and dose-dependently (p < 0.05) reduced the GSH level in the plasma and the whole brain when compared with respective control values. Atorvastatin was the least effective statin, as only the high dose achieved a significant reduction in brain GSH level in comparison with the respective control value. Repetitive administration of the three statins at 200 mg/kg of body weight/day for 14 or 28 consecutive days significantly and time-dependently reduced plasma and brain GSH levels in comparison with respective control values. The oxidative stress biomarker MDA level significantly increased in the plasma and brain of mice following single or repetitive treatments with the three statins, and the most effective one was rosuvastatin. In association with these changes, activities of the liver enzymes ALT and AST were also increased in the plasma with single and repetitive statin treatments, and the most effective one was rosuvastatin. Conclusion The data suggest an association of high doses of three statins (atorvastatin, simvastatin, and rosuvastatin) with the induction of oxidative stress manifested as GSH reduction and MDA elevation as adverse effects in the brain and plasma of mice, which suffered from the additional burden of liver injury. These effects could be the basis of an in-depth exploration of statin adverse effects in experimental animals and to find an animal model, probably the mice, for the induction of adverse effects of statins that target the brain, as well as to shed light on potential statin intolerance outcomes following single-dose treatments in this species.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Al-Shalchi,

Mohammad

2024

Cureus

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“…These actions include modulation of the central and peripheral cholinergic system [4,[5][6][7]. Statins have been shown to have different effects on blood or brain cholinesterase (ChE) activity [5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…These actions could be pertinent to the type of statin in use, dosage applied, response of the animal species versus humans, and the type of ChE in the blood or brain tissue-true versus pseudo-ChE [6,[8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the effects of different statins on ChE activity do not appear to be consistent in both in vitro [5,8] and in vivo [6,8,12] studies. The conflicting effects of statins on plasma, erythrocyte, and brain ChE activities have been reported in the form of either increase/decrease, or no effect [6][7][8][9][10][11][12]. The ability of statins to centrally modulate or inhibit ChE activity suggests the possibility of beneficial effects of statins in cases of dementia [4,13].…”

Section: Introductionmentioning

confidence: 99%

“…Considering that the anti-ChE effects of statins were not consistent across the statins/tissues or species examined [6][7][8][9][10][11][12], another aspect of the pleiotropic effects of statins is behavioral modulation in patients and laboratory animals receiving statin therapy. Behavioral effects included aggression, depression, memory loss, and confusion [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Adverse neurobehavioral changes with reduced blood and brain cholinesterase activities in mice treated with statins

Al-Shalchi,

Mohammad

2024

Vet World

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Background and Aim: Pleiotropic effects of hypolipidemic statins with behavioral outcomes have been suggested in humans and laboratory animals. There is limited information on the neurobehavioral effects of statins in mice. The aim of the present study was to examine changes in neurobehavioral performance and cholinesterase (ChE) activity in mice after high doses of three commonly used statins (atorvastatin, simvastatin, and rosuvastatin). Materials and Methods: Two hours after vehicle (control) or statin dosing at 250, 500, 750, or 1000 mg/kg orally, each mouse was subjected to 5 min open-field activity, negative geotaxis at an angle of 45°/60 s, 5 min head pocking, and forced swimming endurance. Plasma, erythrocyte, and brain ChE activities were determined spectrophotometrically 2 and 24 h after oral dosing of statins at 500 and 1000 mg/kg. Results: The statins variably, but dose-dependently and significantly (p < 0.05) delayed the latency to move in the open-field arena, decreased locomotion and rearing, reduced head pocking, and delayed negative geotaxis performance. However, statins significantly increased the duration of forced swimming and decreased the duration of immobility in the swimming tank. Statins significantly and dose-dependently decreased plasma, erythrocyte, and brain ChE activity 2 and 24 h after dosing. Plasma and brain ChE activities recovered by 5%–32.9% and 5.7%–14.4% 24 h later from the 2 h ChE values, respectively. Conclusion: High doses of statins differentially modulate neurobehavioral outcomes in mice in association with reduced plasma, erythrocyte, and brain ChE activity. Plasma or erythrocyte ChE may be used for biomonitoring of the adverse/ therapeutic effects of statins. Keywords: atorvastatin, head pocking, negative geotaxis, open-field activity, rosuvastatin, simvastatin, swimming endurance.

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Modulatory effect of opioid administration on the activity of cholinesterase enzyme: a systematic review of mice/rat models

Aramjoo

Riahi-Zanjani

Farkhondeh

et al. 2021

Environ Sci Pollut Res

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Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats

Cited by 5 publications

References 42 publications

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Oxidative Stress-Induced Adverse Effects of Three Statins Following Single or Repetitive Treatments in Mice

Adverse neurobehavioral changes with reduced blood and brain cholinesterase activities in mice treated with statins

Modulatory effect of opioid administration on the activity of cholinesterase enzyme: a systematic review of mice/rat models

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