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Tohoku J. Exp. Med., 2006, 209,B e
2 a0l Effects of Fluvastatin in Rats Fluvastatin Alters Psychomotor Performance and Daily
Activity but not the Spatial Memory in Rats
SUKRUCAN H. BAYTAN, MEHMET ALKANAT, MEHMET OZEREN,1 MURAT EKINCI2 and AHMET AKGUNDepartment of Physiology, 1Department of Obstetrics and Gynecology, Karadeniz Technical University, Medical School, Trabzon, Turkey, and 2Department of Computer Engineering, Engineering School, Karadeniz Technical University, Trabzon, Turkey BAYTAN, S.H., ALKANAT, M., OZEREN, M., EKINCI, M. and AKGUN, A. Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats. Tohoku J. Exp. Med., 2006, 209 (4), 311-320
Statins, inhibitors of cholesterol synthe- sis for treating dyslipidemia and preventing cardiovascular complications, have been shown to alter central nervous system functions. Our aim was to investigate the effects of the fluvastatin, a member of statin family, on psychomotor performance, daily activity and spatial memory. Sprague-Dawley rats were treated with fluvastatin (n = 8) or placebo as a control (n = 11) regardless of sex. Fluvastatin (7.5 mg/kg) was administered orally once a day for four weeks, while the control group was administered only placebo. Psychomotor performance was measured by rotarod tests. No significant difference was observed in the fluvastatin group over the course of weeks, but the control group preferred to stay on the device shorter times (p < 0.05). For the first three weeks of the drug administration there was a statistical difference between the groups, however no difference was found after the 4th week. There was no difference in the Barnes maze spatial memory test between the groups and also within the groups over the course of time. Daily activity tests revealed that stereotypical and vertical movements of the fluvastatin group were significantly less than the control group in all four weeks. Ambulatory movements and the distances taken by the fluvastatin group were decreased significantly over the course of time (p < 0.005 and p < 0.001, respectively), but the control group did not reveal any significant change. Our results suggest that fluvastatin altered psychomotor performance and daily activity in rats, but it did not affect the spatial memory. These behavioral changes might be associat- ed with alterations in the composition of the brain lipids caused by fluvastatin. statin; fluvastatin; behavior; Barnes maze; psychomotor 2006 Tohoku University Medical Press Statins, inhibitors of the 3-hydroxy-3-meth- al. 2004). Statins change lipid metabolism, lower ylglutaryl-CoA (HMG-CoA) reductase in the syn- low-density lipoproteins, increase high-density thesis of cholesterol, are widely used in the pre- lipoproteins, and decrease tryglicerids depending vention of cardiovascular diseases by decreasing on specific statin used (Schaefer et al. 2004).
blood lipid levels (Maron et al. 2000; Collins et Cholesterol metabolism and transport of Received February 22, 2006; revision accepted for publication May 25, 2006.
Correspondence: Dr. Sukrucan H. Baytan, KTU Tip Fak, Fizyoloji ABD, 61080 Trabzon, Turkey.
S.H. Baytan et al.
cholesterol turnover within the brain were fluvastatin on behavioral changes by evaluating reviewed by Bjorkhem and Meaney (2004). spatial memory, psychomotor performance and Statin applications and lowered plasma cholester- daily activity in Sprague-Dawley rats.
ol levels were found to affect central nervous sys- tem (CNS) functions in humans. Severe irritabili- ty and aggression with statin usage in six patients General procedure were reported by Golomb et al. (2004a, b). They The study was approved by Karadeniz Technical also addressed that there is a need for more data University, Medical School animal ethics committee to establish the impact of hydrophilic and lipo- (12-October-2005 ref: 473).
philic statins on cognition, aggression, and brain Twelve male and twelve female Sprague-Dawley serotonin activity. Cultured glial cel s have HMG- rats with initial weights of 200-240 g, 5-6 months old CoA reductase as the major rate-limiting enzyme were provided and maintained in our vivarium (constant for their synthesis of cholesterol (Snipes and Suter temperature of 23 ± 1°C; 60 ± 10% relative humidity; 1997). A well known fact is that myelination is 12-h/12-h light cycle; food and water ad lib.). The ani- preceded by increased esterification of cholesterol, mals were kept in our vivarium for two weeks for habitu- which is possibly a mechanism for accumulation ation without any testing and training. The animals were of the required very high amounts of cholesterol divided into two groups (6 males and 6 females in each in the developing CNS (Norton and Cammer group total of 12 animals in each group) as control and 1984). Experimental evidence for a cholesterol fluvastatin groups using the random table. Fluvastatin shuttle from astrocytes to neurons in an in vitro (LescolTM, Novartis, Basel, Switzerland) was obtained commercially and homogenized in phosphate buffered system had been presented by Mauch et al. (2001). saline (PBS). The control group was administered the Benefical effects of atorvastatin on human higher PBS solution without the drug as placebo. The adminis- cortical functions were studied by Parale et al. tered solution volume each time was 0.5 ml in both (2006), which lays strong foundations for future groups. Fluvastatin (7.5 mg/kg once a day) and placebo human studies about mental activities and statin was administered for a total of 28 days orally by gavage usage relationships. These behavioral studies around 8:30 am. Testing was designed as all measure- clearly showed that statin treatment can alter ments were taken once a week on the 0th, 7th, 14th, 21st, behavior with its possible cholesterol altering and 28th days, regardless of sex. Five animals had to be effects in the CNS.
excluded from the study during the testing period, two The effects of several statins on lipid compo- animals died from unknown causes, two animals repeat- sition of the brain in rats, including fluvastatin, edly failed to find the goal box in the Barnes maze, and were observed by Vecka et al. (2004), in which one animal was observed to be pregnant. With the fluvastatin, an important member of the statin excluded animals, the fluvastatin group consisted of 8 family, was shown to increase sphingomyelin and animals (4 males and 4 females). The control group con- to decrease diphosphatidylglycerol contents in rat sisted of 11 (5 males and 6 females) animals for brains. Yet, the most important changes in the fatty acid profile being in the ceramide monohex- osides, lead to a decrease in the content of saturat- Rotarod test (Psychomotor performance) ed fatty acids and an increase in the content of An accelerating rotarod device designed for mice and rats was used for the psychomotor performance eval- polyunsaturated fatty acids. Moreover, it has uation. The rod was 4.5 cm in diameter, covered with been shown that chronic administration of statins non-slippery material, 30 cm above the device floor alters multiple gene expression patterns in the (Commat Inc., Ankara, Turkey). The animals were first mouse cerebral cortex (Johnson-Anuna et al. habituated on the rod and trained for 5 days before test- 2005). From these studies' standpoints, changes ings had started. Each training day the animals were in CNS functions and behaviors could be expect- expected to stay on the rod as long as they could. After ed with statin treatment.
the first fall, it was taken to its homecage to rest for at In this study, we investigated the effects of least 15 min and then the second trial was started. Every Behavioral Effects of Fluvastatin in Rats animal took three trials per day during the training peri- the escape hole was covered by a light tight material and od. The training trials started with the stationary rod for the animal was allowed to stay there for 60 sec. The pro- 60 sec, and then it started to revolve and gradually cedure was repeated four times during each testing peri- increase to 16 rpm. There was no punishment system od. If an animal could not find the hole in 5 min, an that was used on the rotarod tests. After the training experimenter gently drove the animal to the escape hole period and one day resting period, the testing phase was and the animal was allowed to rest there for 60 sec. In started. In the testing phase the same procedure was the training and testing trials, the goal box position applied, except each animal underwent 5 trials in each remained the same between measurements, but maze experiment day. Latency times are measured in seconds.
holes were turned randomly each time for animals to avoid following odor trails. Before and after each test Barnes maze test (Spatial memory and reference learn- and training session, the maze was wiped clean for the same purpose as well. The animals were also trained A modified Barnes maze was utilized to perform once before each experiment day and the hole position spatial learning and reference memory tests described by was changed for each testing week. In the first training Barnes (1979) and Turner et al. (2004). The maze was trial, animals did not know the position of the goal box. 122 cm in diameter made of water resistant white materi- In the testing period, the hole remained in the same posi- al, had 12 holes with a diameter of 9.5 cm equidistant tion. The testing procedure was the same as in the train- from each other, and 3 cm away from the perimeter. ing period, but when the start box was removed, a timer Height of the maze was 140 cm to discourage animals was started. Head pokes or closely approaching and from jumping to the floor. A 10 cm wide, 20 cm long, visually checking the wrong holes by the animals were and 12 cm high stainless steel goal box was placed under counted as errors. Repeated pokes in the same hole or one hole during the training and experiment sessions. several stares to a wrong hole in a single approach were Animals were placed in a light-tight start box placed in counted as one error. The timer stopped when all paws the middle of the maze, equivalent to the goal box. Extra touched the goal box. Four measurements were recorded maze cues were placed around the maze, big round and on each testing day.
square dark colored posters hung on the white wall, and a divider curtain was used to hide the experimenters Daily activity while the tests were being performed. A floodlight was A computerized cage system for animal activity was used 180 cm over the maze for aversive reaction on tests. used to assess 24-hr daily locomotor activity, such as A video system, which was used for recording animal ambulatory movements, vertical movements, stereotypi- movements, was attached on top of the maze. A televi- cal movements, and distances were taken in centimeters sion monitor was located behind the divider curtain. The (Commat Inc.). The cage was a clear cube (each side 42 video recordings were evaluated offline to calculate the cm). Horizontal infrared beam rays on each four sides distance taken by the animals. Distance measurements (2.5 cm apart to each other, 2.5 cm in height) monitored were calculated by using the Software developed by and the horizontal movements. There was also a similar the Department of Computer Science and the Department beam design in the height of 13 cm to record vertical of Physiology, Medical School in Karadeniz University.
movements of the animal. Stereotypical movements Before the tests began, all animals were allowed to such as itching, sniffing and head bobbings were record- stay on the Barnes maze for one hour moving freely ed. Also the numbers of horizontal movements in the without the goal box for habituation. Afterwards, 4 train- cage (ambulatory) were counted, while stereotypical or ing sessions for 5 days were conducted. Each animal vertical movements were excluded in the ambulatory was brought to the testing laboratory separately. After a counts. Vertical movements, and the total horizontal dis- five minute resting period, it was placed under the start tances taken by the animals (distance) were calculated.
box and kept there for 10 sec with their heads always The data within the control and fluvastatin groups in positioned to the north. Lights were turned on, experi- the proceeding weeks were statistically evaluated with menters moved behind the divider, and then the start box the Friedman test. These groups were compared with was removed remotely by a pulley system and the each other separately every week from week zero animals were expected to find the goal box. When the through week four by Mann-Whitney's U-test. A p-value animal found the escape hole, the lights were turned off, of smaller than 0.05 (p < 0.05) was considered to be S.H. Baytan et al.
significant. Statistical analysis was performed by statisti- no difference observed after the 4th week.
cal program package, SPSS version 13.01 (Lead Technologies Inc., Chicago, IL, USA).
Barnes maze test There was no difference between the fluvas- tatin and the control group for errors, latency Rotarod test times and distances (p > 0.05, Table 2). Also, The fluvastatin group showed no significant comparisons between the fluvastatin and placebo difference over the course of the weeks while the groups for four weeks indicated there was no sig- control group stayed on the rotarod device for nificant difference between the groups.
shorter times over the course of time (p < 0.05, Table 1). As expected, there were no differences Daily activity tests observed in the 0th week. While after the 1st, 2nd All data about daily activity tests are shown and 3rd weeks a difference was found, there was in the Table 3.
TABLE 1. Latency times of fluvastatin and control groups on the rotarod device §.
§ Latency times were expressed in seconds.
The Data are in mean ± S.E.M. format. * p < 0.05.
† p values within the groups by the Friedman test.
†† p values between the groups for each week by the Mann-Whitney's U-test.
TABLE 2. Barnes maze error counts, latency times and distances for each week in the groups §.
Distance (cm) Control §Error counts on the Barnes maze, latency times for entering right hole in seconds, and distances taken on the maze in centimeters.
The Data are in mean ± S.E.M. format.
† p values within the groups by the Friedman test.
†† p values between the groups for each week by the Mann-Whitney's U-test.
Behavioral Effects of Fluvastatin in Rats TABLE 3. Daily activity measurements for fluvastatin and control groups§.
Stereotypical Control 10,580 ± 974 11,707 ± 890 11,382 ± 1,013 11,432 ± 884 11,344 ± 914 Ambulatory Control 8,434 ± 734 8,259 ± 1,032 8,639 ± 1,209 8,939 ± 1,437 8,514 ± 1,319 0.91 5,954 ± 594 6,722 ± 1,048 0.000* § Counts of stereotypical, ambulatory, vertical and horizontal movements, and distances taken in centimeters, in the daily activity cage.
The Data are in mean ± S.E.M. format. *p < 0.05.
† p values within the groups by the Friedman test.
†† p values between the groups for each week by the Mann-Whitney's U-test.
Stereotypical movements. During the course found to take less distance during the course of of time no difference was shown statistically in time (p < 0.001), but no change was observed in either group. When the difference between the control group. When the difference between groups was analyzed each week, the fluvastatin groups over the weeks was investigated, no statis- group was found to make less stereotypical move- tical difference between the groups was observed.
ments from the 1st week to 4th week.
From the results, psychomotor performance Ambulatory movements. The fluvastatin was found to be altered in the control group group was found to have less ambulatory move- during the course of the time that they ran on the ment counts during the course of time (p < 0.005), rotarod device for shorter time periods. Between but the same significance was not observed for the the 1st and the 3rd weeks, a significant difference control group. When the difference between the was observed between the control and fluvastatin groups was investigated on a weekly basis, the groups. But, the fluvastatin group did not change fluvastatin group was found to have less ambula- their psychomotor performance during the course tory movements only on the 3rd week.
of the time. Spatial memory was not affected by Vertical movements. During the course of fluvastatin use, according to the Barnes maze time no difference was observed statistically in measurements. The results of daily activity tests either group. When the difference between the revealed that the fluvastatin group made less groups was investigated for each week, the fluv- ambulatory movements and took less distances astatin group was found to have less vertical during the course of time. When compared to the movements from the 1st week to 4th week.
control group, the fluvastatin group displayed Total distance. The fluvastatin group was stereotypical and vertical movements that were S.H. Baytan et al.
found to be significantly less in the last four drug with aggression (Golomb et al. 2004b).
administered weeks.
Fluvastatin is known as a lipophilic drug (De Angelis 2004). Effects of fluvastatin in the rat brain were shown by Vecka et al. (2004). Another It has been suggested that statins may pro- study reported that lovastatin and simvastatin vide beneficial effects that are not limited to strongly reduced the levels of free cholesterol in reduced levels of low-density lipoproteins and tri- synaptozomal plazma membranes and lovastatin glycerides in the blood (Liao 2002, 2004, 2005). and pravastatin significantly reduced cholesterol Statins are expected to affect any organ or system levels in the exofacial membrane leaflet. These involved in lipid metabolism, including the CNS, changes were accompanied by modified mem- which has a concentration of unesterified choles- brane bulk fluidity.
terol higher than any other tissue (23 mg/g), con- Statins reduce the expression of the raft taining 23% of the sterol present in the whole marker protein flotillin. Statins directly or indi- body pool in humans while accounting for only rectly exert various effects on cell membrane cho- 2.1% of body weight. The relationships between lesterol homeostasis in the CNS (Kirsch et al. plasma cholesterol concentration and sterol 2003). A rat brain perfusion study demonstrated metabolism in the CNS or cognitive functions in that fluvastatin crosses blood brain barrier with the brain remain unclear (Dietschy and Turley permeability coefficient of 2.5 × 10 (-4) (Guillot 2004). There are reports of the effects of statins et al. 1993). Some other statins cross the blood on cognitive functions in patients with primary brain barrier to a much greater extent. These hypercholesterolemia (Gengo et al. 1995). studies suggest that statins affect brain lipid com- Another study suggested that lovastatin treatment position, cell membrane and cholesterol homeo- might cause small performance decrements on stasis; hence CNS functions cause behavioral neuropsychological tests of attention and psycho- motor speeds, but in the same study no evidence Fluvastatin usage did not affect the spatial was found in psychological distress or substantial memory and reference learning in the rats in our cognitive function alterations in hypercholesterol- study. Even though a study indicated that emic adults. Another study, comprising of 308 Atorvastatin treatment promoted the restoration of hypercholesterolemic adults, suggested that there spatial memory function in rats with traumatic are minor decrements in cognitive functioning brain injury, this might be a result of increased with simvastatin treatment (Muldoon et al. 2000, blood flow after the injury (Lu et al. 2004). 2004). However, two cases were reported to have Existing reports are not sufficient to make clear significant temporary cognitive impairment relat- conclusions about the memory effects of the statin ed to statin therapy (King et al. 2003). A review usage in animals and humans. The effects of of a literature study about statin-associated statin administration on memory and learning in memory loss of 60 cases using Med-Watch drug rats are less than clear.
surveillance system of the Food and Drug Our results on daily activity tests that the flu- Administration between November 1997 and vastatin group made less movements during the February 2002 was presented by Wagstaff et al. course of time compared to the control group sug- (2003). Severe irritability and aggression with gested that these results may be related to a mus- statin usage in six patients were also reported by cle injury caused by fluvastatin use. It was shown Golomb et al. (2004a). There is an ongoing dou- that fluvastatin inhibits Rho/Rho-kinase signalling ble-blind, placebo-controlled clinical trial with and causes disruption of the actin cytoskeleton in selected 1,000 non-cardiac patients that will be rat smooth muscle cultures (Kato et al. 2004). In available for assessing the impact of the statins in some cases, side effects occur in skeletal muscle, cognitive functions, personality, sleep, behavioral including myositis or even rhabdomyolysis. irritability, and blood serotonin levels correlated Simvastatin causes apoptosis in differentiated Behavioral Effects of Fluvastatin in Rats human skeletal muscle cells (Sacher et al. 2005). the noradrenergic fibers of the locus coeruleus, The potential role of the depleted isoprenoid pool and serotonergic fibers from the median raphe in the pathophysiology of statin myopathy is (Gray 1994).
discussed by Baker (2005).
According to Gray (1990), the hippocampus If a muscle injury was present with fluvas- is an important contributor to the BIS, causing the tatin treatment, we would expect less activity and individual to stop and attend to environmental shorter walking time from the fluvastatin group in cues forwarded from other brain structures. the rotarod tests. But the fluvastatin group did not Information processed by the hippocampus is show this type of behavior and preferred to stay joined in the hypothalamus with information and walk on rotarod for periods of longer time. processed by a brain structure called the septum. These results suggest that fluvastatin may alter The hypothalamus generates behavioral respons- psychomotor behavior at higher cortical or spinal es. The role of the amygdala in this system is to levels. With applied rotarod device tests, anxiety give emotional response based on conditioning to may be elicited by stimuli associated with the stimuli that predict the occurrence of reinforce- omission or loss of reward. Since neither reward ment. The BIS is in part moderated through nor a punisment is employed during tests, this the action of the neurotransmitter Gamma- might invoke a state of anxiety state in the sub- aminobutyric acid (GABA) on the ascending jects and activate the Behavioral Inhibition noradrenergic and serotonergic pathways to the System (BIS) proposed by Gray (1991).
hippocampus. GABA is mostly inhibitory and it The Behavioral Approach System (BAS) is involved in the regulation of behavior. Rats activates approach behaviors in response to cues demonstrated a weakened emotional response for reward or non-punishment (Gray 1994). It after the hippocampus was lesioned, and GABA may be neurophysiologically associated with the increases in the nucleus accumbens were blocked motor programming systems in the CNS. The during the acquisition and expression of a condi- key components are the basal ganglia, the dopa- tioned emotional response (Saul'skaia and minergic fibers that ascend from the mesencepha- Gorbachevskaia 1998). Increases in GABA levels lon to innervate the basal ganglia, thalamic nuclei in the amygdala mitigate the intensity of anxiety. closely linked to the basal ganglia and similarly GABAergic neurons are modulated by dopami- neocortical areas such as motor, sensorimotor, and nergic and noradrenergic input from the nucleus prefrontal cortex which are also closely linked to accumbens (Steiniger-Brach and Kretchmer the basal ganglia. Dopamine is known to play an 2005). Once BIS was activated, predictions were essential moderating role in the functioning of the made based on memories of previous experience BAS (Depue and Iacono 1989).
provided by the prefrontal cortex. The memory- BIS is the main cortical behavioral inhibitory based predictions were then compared with events system. Signals of punishment, non-reward, occurring in the present. Incongruence between novel stimuli, and innate fear stimuli lead to the prediction and reality results in behavioral behavioral inhibition, an increment in tense arous- inhibition and increased physical arousal and al, and increased attention. The BIS may be con- attention, the individual searches for more infor- sidered both as a cognitive and physiological sys- mation (Gray 1994).
tem (Fowles 1988; Gray 1991). Cognitively, the Dopamine and acetylcholine were used in role of the BIS is to compare the current state of the nucleus accumbens according to Gray (1990). the world with expectations and to inhibit and In the BAS the nucleus accumbens is involved in modify behavior that leads to deviations from general incentive motivation for approach behav- expectation. Physiologically, the comparator ior. The path between the nucleus accumbens and function of the BIS is associated with the septo- the ventral tegmental area of the brain (where hippocampal system. Input to this system comes dopamine is present) allows motive to be translat- from the prefrontal cortex output flows through ed to behavior through dopaminergic relay of S.H. Baytan et al.
input to the prefrontal cortex as presented by Lee be either or both results of loss of motor cortical et al. (1998).
neurons and possible muscle damage by high It has been reported that high doses of simv- dose of fluvastatin treatment. This is caused by astatin upregulate dopamine D1 and D2 receptor apoptosis in differentiated human skeletal muscle expression in the rat prefrontal cortex by a possi- cells (Sacher et al. 2005) or statin affected NMDA ble involvement of endothelial nitric oxide syn- receptor functions. Local dopaminergic modula- thase (Wang et al. 2005). Protective effects of tion of the motor activity induced by NMDA fluvastatin from the 1-methyl-4-phenylpyridine receptor stimulation in the ventral hippocampus induced hydroxyl radical generation in the rat was shown by Gimenez-Llort (2002).
striatum in cultured cells is reported (Obata and Our results suggest that fluvastatin might Yamanaka 2000).
affect psychomotor performance and daily activi- From our results we can speculate that fluv- ty in rats, but not the spatial memory. We con- astatin treated rats ran longer times on the rotarod clude that unreduced pscyhomotor performance in caused by either prefrontal cortical neuron loss the fluvastatin group in contrast to the control from the BIS related prefrontal association areas group may be associated with altered BIS and resulted in decreased BIS activity or increased BAS under the effects of the fluvastatin in the BAS activity lead by increased cortical dopami- brain. Daily activity changes are suggested to be nergic activity, which might be the cause of the results of the reduced dopaminergic activity along decreased inhibited reaction towards a stressful with cortical lipid profile changes or with possible stimulus. There is a possibility that these mecha- muscle damage of the fluvastatin. Further behav- nisms might have been worked together.
ioral and receptor level neural studies are needed BAS or BIS is not in effect in daily activity to explain these effects.
evaluations, because there is no reward or punish- ment stimulus involved in this type of test. Atorvastatin attenuated the glutamate-induced Special thanks to Ozturk Medical Inc., Trab- increase of intracellular calcium, which was asso- zon-Turkey for the financial support of this study.
ciated with a modulation of N-methyl-D-asparate We also like to thank Mr. Kemal Uzun for his (NMDA) receptor functions (Boesel et al. 2005). enormous helpful efforts in the studies.
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