Comparative study of the effect of atorvastatin on learning and memory in two different experimental models of impaired memory Maria Georgieva - Kotetarova, Ivanka Kostadinova Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Medical University – Plovdiv, Bulgaria Correspondence to: [email protected]
25 saline 1 ml/ 100g
Introduction bw 20 Frequent and prolonged use of statins as lipid-lowering agents raises the saline+ diazepam 2,5 mg/kg issue of their pleiotropic effects and the need to extend their clinical + 15 indications. In the past decade data has emerged supporting their + saline+NaNO2 50 neuroprotective effect. Clinical studies have demonstrated that cognitive + mg/kg 10 + decline is slowed in Alzheimer patients receiving statins [1]. Learning + AT10 mg/kg + 5 + + diazepam 2,5 ability and memory retention have been found to improve after treatment + mg/kg with statins in experimental models of vascular dementia and scopolamine- responsesof unconditionedNumber AT 10 mg/kg + induced amnesia [2,3]. 0 NaNO2 50 mg/kg day 1 day 2 day 3 day 4 day 5 day 12 Aim Fig. 2 – Effect of atorvastatin on the number of unconditioned responses in active avoidance test – shuttle box The aim of the present study was to investigate the effect of atorvastatin on learning and memory in two different models of impaired memory – In the active avoidance test animals treated with atorvastatin and diazepam nd rd diazepam-induced amnesia and hypoxia induced by sodium nitrite. showed increased number of conditioned responses on the 2 (p=0.045), 3 th th (p=0.049), 4 (p=0.011) and 12 day (p=0.005) compared to the group with Methods and Materials diazepam (fig.1). No significant difference in the number of unconditioned In the present study Male Wistar rats with mean weight 180-200g were responses was found between the group treated with atorvastatin and used. The animals were kept under standard laboratory conditions diazepam and the animals with diazepam-induced amnesia (fig.2). In the (temperature 26 ±1.00 , humidity 45%, light/dark cycle 12/12 hours) and step-trough passive avoidance test atorvastatin-treated animals with had received water and food ad libitum. Our study has been approved by diazepam-induced amnesia improved short- (p=0.021) and long-term the ethic committee of Medical University-Plovdiv and by the Bulgarian memory retention (p=0.015) (fig.3). In the step-down passive avoidance test Food Safety Agency. The animals were divided into 5 groups (n=8) as animals treated with atorvastatin and diazepam showed improved long-term follows: memory (p=0.008) compared to the group, receiving diazepam (fig.4). 1st – saline 1ml/ 100g per os (p.o.); There was no significant difference in the studied parameters between the 2nd – saline 1ml/ 100g p.o. and diazepam 2,5 mg/kg bw intraperitoneally atorvastatin-treated animals with sodium nitrite-induced hypoxia and the (i.p.); group with sodium nitrite in active and passive avoidance tests. 250 rd 3 – saline 1ml/ 100g p.o. and sodium nitrite 50 mg/kg bw saline 1 ml/ 100g * 200 subcutaneously (s.c.); + * th + + + 4 – atorvastatin 10 mg/kg bw p.o and diazepam 2,5 mg/kg bw saline+ Diazepam 2,5 intraperitoneally (i.p.); 150 mg/kg 5th – atorvastatin 10 mg/kg bw p.o sodium nitrite 50 mg/kg bw saline+NaNO2 50 100 subcutaneously (s.c.); time Latency mg/kg AT10 mg/kg bw+ Atorvastatin 10 mg/kg bw and saline were administered for 14 days before 50 Diazepam 2,5 mg/kg causing memory impairment. Diazepam was administered before training sessions to cause anterograde amnesia [4]. Sodium nitrite was used to 0 AT 10 mg/kg bw+ day 1 day 2 day 3 day 9 NaNO2 50 mg/kg induce hypoxia which causes brain damage similar to that of aging brain [4]. Learning ability and memory retention were evaluated using active Fig. 3 – Effect of atorvastatin on the latency of reactions in step-through passive avoidance test - automatic reflex conditioner (shuttle box) and two passive avoidance test 70 avoidance tests (step-through and step-down) (Ugo Basile, Italy). In the * saline 1 ml/ 100g active avoidance test learning session consisted of 5 consecutive days. 60 50 saline+ Diazepam 2,5 Memory retention test was performed on day 12. The following behavioral + mg/kg reactions were investigated: conditioned responses, unconditioned 40 + saline+NaNO2 50 responses and intertrial crossings. In both passive avoidance tests training 30 mg/kg
th time Latency sessions consisted of two consecutive days and on the 3 day short-term 20 AT10 mg/kg + Diazepam 2,5 mg/kg memory was evaluated. Long-term memory retention test was performed 10
on day 9 and day 7 for step-through and step-down respectively. The 0 AT 10 mg/kg+ NaNO2 50 mg/kg latency of reactions was used as criterion for learning and retention for day 1 day 2 day 3 day 7 both passive avoidance tests. The statistical analyses were performed using Fig. 4 – Effect of atorvastatin on the latency of reactions in step-down passive ANOVA followed by Tukey’s multiple range test. avoidance test Conclusions Results The results from our study suggest that atorvastatin 10 mg/kg bw improves 25 saline 1 ml/ 100g learning abilities and memory retention in animals with diazepam-induced * amnesia. In the experimental model of sodium nitrite-induced hypoxia 20 atorvastatin could not reverse the memory impairment. Our results suggest * saline + diazepam 2,5 mg/kg that improvement of cognitive function by atorvastatin depends on the 15 * degree of brain damage. Sodium nitrite 50 mg/kg bw causes severe saline+NaNO2 50 mg/kg memory impairment that could not be ameliorated with atorvastatin. 10 * + References + AT10 mg/kg+ 1. Masse, I., Beordet, R., Deplanque, D., Al Khedr, A., Richard, F., Libersa, C., Pasquier, F., 2005 Lipid lowering drugs are
Number responsesof conditionedNumber 5 Diazepam 2,5 mg/kg associated with a slower cognitive decline in Alzheimer’s disease, J Neurol Neurosurg Psychiatry. 76(12):1624-1629. 2. van der Most, P., Dolga, A., Nijholt, I., Luiten, P., Eisel, U., 2009 Statins: Mechanisms of neuroprotection, Prog Neurobiol. + + + + + + 88(1):64-75 + + + AT 10 mg/kg + 0 NaNO2 50 mg/kg 3. Javadi-Paydar, M., Rayatnia, F., Fakhraei, N., Zakeri, M., Mirazi, N., Norouzi, A., Dehpour, A.R., 2011 Atorvastatin improved scopolamine-induced impairement in memory acquisition in mice: Involvement of nitric oxide. Brain Res. day 1 day 2 day 3 day 4 day 5 day 12 1386:89-99. 4. Petkov VD, Biology of memory. In: Petkov VD, 1998 The problem of memory – Achievements and Prospects, Sofia, Fig. 1 – Effect of atorvastatin on the number of conditioned responses in active “Prof . Marin Drinov” Academic Publishing House: 23-129. avoidance test – shuttle box Disclosure statement: This poster represents no potential conflict of interest P.1.g.070 Comparative study of the effect of atorvastatin on learning and memory in two different experimental models of impaired memory M. Georgieva-Kotetarova1, I. Kostadinova1 1Medical Universitya Pharmacology and Clinical Pharmacologya Plovdiva Bulgaria
Purpose: Frequent and prolonged use of statins as lipid-lowering agents raises the issue of their pleiotropic effects and the need to extend their clinical indications. In the past decade evidence has emerged supporting their neuroprotective effect. Clinical studies have demonstrated that cognitive decline is slowed in Alzheimer patients receiving statins [1]. Learning ability and memory retention have been found to improve after treatment with statins in experimental models of vascular dementia and scopolamine-induced amnesia [2,3]. The aim of the present study was to investigate the effect of atorvastatin on learning and memory in two different models of impaired memory – diazepam-induced amnesia and hypoxia induced by sodium nitrite.
Methods: Male Wistar rats were divided into 5 groups (n=8). Groups 1, 2 and 3 were treated with saline per os (p.o.) 1ml/100g as follows: 1st – saline only; 2nd – saline and diazepam 2.5mg/kg bw intraperitoneally (i.p.); 3rd – saline and sodium nitrite 50mg/kg bw subcutaneously (s.c.). Atorvastatin 10mg/kg bw was administered orally to group 4 and 5 for 14 days before the beginning of the experiments. Group 4 received also diazepam 2.5mg/kg bw i.p. and the 5th – sodium nitrite 50mg/kg bw s.c. Learning ability and memory retention were evaluated using active avoidance test – automatic reflex conditioner (shuttle box) and two passive avoidance tests (step-through and step-down). In the active avoidance test learning session consisted of 5 consecutive days. Memory retention test was performed on day 12. The following behavioral reactions were investigated: conditioned responses, unconditioned responses and intertrial crossings. In both passive avoidance tests training sessions consisted of two consecutive days and on the 3th day short-term memory was evaluated. Long-term memory retention test was performed on day 9 and day 7 for step-through and step-down respectively. The latency of reactions was used as criterion for learning and retention for both passive avoidance tests. The statistical analyses were performed using ANOVA followed by Tukeyas multiple range test.
Results: In the active avoidance test animals treated with atorvastatin and diazepam showed increased number of conditioned responses on the 2nd (p=0.045), 3rd (p=0.049), 4th (p=0.011) and 12th day (p=0.005) compared to the group with diazepam. No significant difference in the number of unconditioned responses was found between the group treated with atorvastatin and diazepam and the animals with diazepam-induced amnesia. In the step-through passive avoidance test atorvastatin-treated animals with diazepam-induced amnesia improved short- (p=0.021) and long-term memory retention (p=0.015). In the step-down passive avoidance test animals treated with atorvastatin and diazepam showed improved long-term memory (p=0.008) compared to the group, receiving diazepam. There was no significant difference in the studied parameters between the atorvastatin- treated animals with sodium nitrite-induced hypoxia and the group with sodium nitrite in active and passive avoidance tests.
Conclusion: The results from our study suggest that atorvastatin 10mg/kg bw improves learning abilities and memory retention in animals with diazepam-induced amnesia. In the experimental model of sodium nitrite- induced hypoxia atorvastatin could not reverse the memory impairment.
1. Masse, I., Beordet, R., Deplanque, D., Al Khedr, A., Richard, F., Libersa, C., Pasquier, F., 2005 Lipid lowering drugs are associated with a slower cognitive decline in Alzheimeras disease, J Neurol Neurosurg Psychiatry. 76(12):1624–1629.
2. van der Most, P., Dolga, A., Nijholt, I., Luiten, P., Eisel, U., 2009 Statins: Mechanisms of neuroprotection, Prog Neurobiol. 88(1):64–75.
3. Javadi-Paydar, M., Rayatnia, F., Fakhraei, N., Zakeri, M., Mirazi, N., Norouzi, A., Dehpour, A.R., 2011 Atorvastatin improved scopolamine-induced impairement in memory acquisition in mice: Involvement of nitric oxide. Brain Res. 1386:89–99.
Citation: Eur Neuropsychopharmacol. 2014;24aSuppl 2):S244
Keywords Neuropharmacology Behavioural pharmacology Animal models