Differential effects of statins on plasma and brain cholinesterase activities in chicks

Abstract

Statins used to treat dyslipidemia may differentially modulate cholinesterase (ChE) activity impacting neuronal function. This study examines the effects of three statins (atorvastatin, fluvastatin, and simvastatin) on plasma and brain ChE activities and cholesterol levels in a chick model of 7-14 days old. Chicks were dosed orally with single doses of each statin at 50, 100, and 200mg/kg or repeated doses at 100mg/kg/day for 14 consecutive days. Plasma and whole brain ChE activities were measured electrometrically, whereas cholesterol levels were measured using a commercial colourimetric kit. In vitro ChE inhibition by the statins was initiated at 37°C for 10 mins. Data were statistically analysed using analysis of variance followed by the least significant difference test. Atorvastatin and fluvastatin did not significantly affect plasma ChE activities 2 hours after the oral administration, whereas simvastatin at 100 and 200mg/kg significantly increased (28% and 16%, respectively) plasma ChE activity. Repeated oral doses of the statins did not significantly affect plasma ChE activity. However, only simvastatin significantly decreased whole brain ChE activity by 33%. Repeated treatments with the three statins significantly reduced cholesterol levels in the plasma but not in the whole brain. The three statins inhibited in vitro plasma and whole brain ChE activities by 10-33% and 8-43%, respectively. The results suggested that the statins differentially modulated ChE activity in vivo and in vitro in chicks. Additional in vivo studies are warranted on statin effects on ChE activity in different brain regions of animal models.

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

“…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 indepth exploration of an animal model for single-dose statin intolerance is warranted.…”

“…These adverse effects include but are not limited to myotoxicity, neurotoxicity, liver and kidney toxicity, as well as many biochemical alterations [3][4][5][6][7]. Many studies in experimental animals have also supported and documented adverse effects of statins, such as neurobehavioral and locomotive changes [8][9][10][11], impairment of neuromuscular function [12], and alterations in the cholinergic system [10,13]. More recently, we have found adverse effects of statins to be associated with diverse neurobehavioral changes and reduced brain and blood cholinesterase activity in mice [14].…”

“…Various mechanistic investigations have indicated the involvement of several exacerbated biochemical events in the induction of statin intolerance, adverse effects, and toxicity. For example, adverse/toxic outcomes of statins may include reduced blood or tissue cholinesterase activities [10,13,14], hyperkalemia [18], impaired mitochondrial function [19], and generation of reactive oxygen species causing oxidative stress [20]. Hepatocellular liver injury with concomitant elevations of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase have been seen during various therapeutic applications of statins irrespective of the duration of therapy [21].…”