Statins enhance cognitive performance in object location test in albino Swiss mice: Involvement of beta-adrenoceptors

Abstract

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby inhibiting cell synthesis of cholesterol and isoprenoids. Moreover, several studies have been evaluating pleiotropic effects of statins, mainly because they present neuroprotective effects in various pathological conditions. However, knowledge about behavioral effects of statins per se is relatively scarce. Considering these facts, we aimed to analyze behavioral responses of atorvastatin or simvastatin-treated mice in the open field test, elevated plus maze and object location test. Atorvastatin treatment for 7 consecutive days at 1 mg/kg or 10 mg/kg (v.o.) or simvastatin 10 mg/kg or 20 mg/kg enhanced cognitive performance in object location test when compared to control group (saline-treated mice). Simvastatin effects on mice performance in the object location test was abolished by post-training infusion of the beta-adrenoceptor antagonist propranolol. Atorvastatin and simvastatin did not change the behavioral response in open field and elevated plus-maze (EPM) tests in any of the used doses. These data demonstrate the positive effects of both statins in cognitive processes in mice, without any alteration in locomotor parameters in the open field test or anxiolytic-like behavior in EPM. In conclusion, we demonstrate that atorvastatin and simvastatin per se improve the cognitive performance in a rodent model of spatial memory and this effect is related to beta-adrenergic receptors modulation.

Can Cholesterol Metabolism Modulation Affect Brain Function and Behavior?

“…Interestingly, these effects were accompanied by changes in the activity of specific prenylated proteins, Rab3, and RhoA, which share with cholesterol the same biosynthetic pathway and are involved in neurotransmitter release and synaptic plasticity, respectively (Segatto et al, ). Similar behavioral results have been found in mice: in particular, chronic treatment with atorvastatin or simvastatin enhanced cognitive performance in the object location test in albino Swiss mice, but did not induce anxiogenic‐like effects in the elevated plus‐maze test and altered locomotor activity in the open field (Vandresen‐Filho et al, ). Interestingly, prolonged in vitro simvastatin treatment for 2–4 h, but not for 20 min, significantly increased the magnitude of LTP at CA3‐CA1 synapses, without altering basal synaptic transmission or the paired‐pulse facilitation ratio in hippocampal slices of C57BL/6 mice, suggesting a possible mechanism underlying the beneficial effects induced by simvastatin on cognitive function (Mans et al, ).…”

Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin‐Induced Sporadic Alzheimer’s Disease in Mice

“…The positive effect of simvastatin on cognition is attributed to the restoration of cholesterol homeostasis, since elevated cholesterol levels may result in A β formation and cognitive impairment [ 38 ]. In addition, the protective effects of simvastatin may also be related to its ability to diminish brain ischemia, prevent cholinergic neuronal loss, modulate brain-derived neurotrophic factor expression, and promote nitric oxide synthesis [ 28 ].…”

“…Groups III to VI received one ICV STZ injection (3 mg/kg), and group III was treated with simvastatin (20 mg/kg, p.o.) suspended in Tween 80 with 0.9% saline 5 h after STZ injection and then daily for a total of 21 doses [ 28 ]. Groups IV to VI were treated with PFT (100 mg, 300 mg, and 600 mg/kg, p.o., respectively) suspended in Tween 80 with 0.9% saline 5 h after STZ injection and then daily for a total of 21 doses ( Figure 1 ) [ 29 ].…”

Effects of Statins on Renin–Angiotensin System

“…Atorvastatin also increased β-adrenergic receptor density in rat cardiac myocytes and α(1D)-adrenoceptor mRNA expression in the rat aorta [ 102 , 103 ]. In diabetic rats receiving oral atorvastatin, the protein expression of β1-adrenoceptor increased and β1/β3-adrenoceptor ratio changed [ 104 ]. Atorvastatin and simvastatin also improved cognitive performance in a mouse model of spatial memory by modulating β-adrenergic receptors [ 105 ].…”