Simvastatin Impairs Spatial Memory in Rats at a Specific Dose Level

Abstract

Statins, inhibitors of cholesterol synthesis, are used to prevent cardiovascular complications. Moreover, statins have been shown to influence some cognitive functions. The modulating effects of simvastatin, one member of the statin family, on memory-related neurotransmitters and neuronal structures have also been reported. We aimed to investigate the behavioral effects of long-term simvastatin application on daily activity, psychomotor performance and spatial memory using Sprague-Dawley rats. Simvastatin (10 or 30 mg/kg/day) was administered orally to rats, in parallel with a vehicle-treated group. Daily activity test results of both simvastatin groups were found similar to the vehicle group after five weeks of simvastatin or vehicle application. Psychomotor performance was measured with the rotarod test. After 6 weeks of simvastatin or vehicle application, the vehicle-treated group stayed on the rotarod device for a shorter time compared with both simvastatintreated groups. Spatial memory was evaluated by the Barnes maze test. Four weeks of 10 mg/kg/day simvastatin application led to poorer scores on spatial memory compared to the vehicle group, but surprisingly, this effect was not seen in the 30 mg/kg/day group. Our results revealed that simvastatin administration had no significant effect on daily activity. Psychomotor performance test results suggested that simvastatin alters psychomotor behavior at higher nervous system levels. Spatial memory test results indicate that longterm simvastatin usage impairs spatial memory only at 10 mg/kg/day dose. Barnes maze; behavior; statins; brain; locomotor.Tohoku

Simvastatin Treatment Highlights a New Role for the Isoprenoid/Cholesterol Biosynthetic Pathway in the Modulation of Emotional Reactivity and Cognitive Performance in Rats

“…Statins are strong HMGR inhibitors widely prescribed in therapies against hypercholesterolemia and their benefits in preventing atherosclerosis and other cardiovascular diseases are incontrovertible. Recently, it has been reported that high-dose statin treatment induces effects in emotional, learning, and memory processes (Kilic et al, 2012;Douma et al, 2011;Baytan et al, 2008;While and Keen, 2010). However, the role of the MVA biosynthetic pathway in the modulation of emotional behavior and cognitive performance is still unclear because of the lack of systematic studies on the causal link between the activation of this metabolic pathway and behavioral and cognitive outcomes.…”

Simvastatin Promotes Cardiac Myocyte Relaxation in Association with Phosphorylation of Troponin I

“…Control animals received equivalent volumes of saline by the same route. In the rat statins are generally given by oral gavage, to mimic the situation in the clinic whereby the inactive simvastatin lactone is hydrolyzed in the liver to the open acid active form of the drug (Gazzerro et al, 2012), at doses between 10 and 60 mg/kg/day (e.g., Delbosc et al, 2002; Baytan et al, 2008; Renno et al, 2015). …”

Chronic Pravastatin but Not Atorvastatin Treatment Impairs Cognitive Function in Two Rodent Models of Learning and Memory

“…Drugs were administered between 4 and 5pm daily, at least 2 hrs after testing and 16hrs before the next behavioural experiment. The choice of dose was based on previous behavioural studies using statin treatments ( [28] 1, 5mg/kg [21]; 10 and 30 mg/kg [29]; 10mg/kg). Clinical trial doses of pravastatin and atorvostatin are in the region of 40mg and 10mg respectively, in line with the higher relative potency of atorvastatin [30].…”

“…In addition, simvastatin enhances long-term potentiation (LTP) in hippocampal slices in vitro and stimulates hippocampal neurogenesis and expression levels of neurotrophic factors such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) [18–20]. With the exception of a recent study by Baytan et al (2008) [21], demonstrating a statin-induced impairment of spatial memory in naïve rats, data regarding the effects of statin treatment in vivo without prior manipulation of cognitive function is lacking. Since cholesterol is essential in the myelination of neurons and other neuronal functions, it has been proposed that excessive inhibition of cholesterol synthesis could lead to adverse cognitive effects [22].…”