Oral simvastatin for 3 continuous months improves learning and memory ability of chronic cerebral hypoperfusion rats

doi:10.3969/j.issn.2095-4344.2708

Abstract

Abstract:

BACKGROUND: Chronic cerebral hypoperfusion is significantly associated with cognitive decline. Our previous studies have found that mitochondrial aging, increased silent synapses and α-synuclein are important pathological changes of chronic cerebral hypoperfusion. Simvastatin is a traditional lipid regulation agent that can traverse the blood brain barrier, and exerts anti-atherosclerosis, anti-thrombosis and anti-inflammatory effects to improve cognitive function.

OBJECTIVE: To observe the effect of continuous oral simvastatin for 3 months on cognitive function of chronic cerebral hypoperfusion male Sprague-Dawley rats, and explore the clinical significance of simvastatin in preventing and treating vascular cognitive impairment and dementia.

METHODS: Sprague-Dawley rats were randomly divided into model group, sham group, solvent group and simvastatin group. In the model group, rats were subjected to bilateral common carotid artery occlusion. In the sham group, the bilateral common carotid arteries were not ligated. In the solvent group, the model rats were intragastrically treated with 0.5% carboxymethyl cellulose sodium. In the simvastatin group, the model rats were intragastrically treated with simvastatin suspension. Interventions in each group lasted for 3 months. Behavioral tests were then used to evaluate the learning and memory ability of rats in each group. The expressions of synaptophysin and post-synaptic density 95, key proteins of presynaptic and postsynaptic membrane, were detected by western blot. Ethical approval was obtained from the Animal Experimental Ethics Committee of the General Hospital of Western Theater Command with approval No. 2019ky79.

RESULTS AND CONCLUSION: Compared with the sham group, the learning and memory functions of the rats in the model group were significantly impaired. In the open-field test, the moving distance within 5 minutes was significantly reduced in the model group compared with the sham group (P < 0.05), suggesting that autonomous exploration behavior was impaired. In the place navigation test, escape latency was significantly shortened in the model group, implicating the reference memory was damaged. In the spatial probe test, the frequency of passing through the platform and the time for passing through target quadrant were reduced, indicating that the space exploration ability was reduced. In the simvastatin group, however, these indexes were all improved. Western blot results showed that the protein expression of synaptophysin and post-synaptic density 95 decreased significantly in the model group (P < 0.05), but increased in the simvastatin group as compared with the solvent group. Therefore, chronic cerebral hypoperfusion can significantly impair learning and memory function and reduce cognitive level in rats. Continuous oral simvastatin for 3 months can improve cognitive function in chronic cerebral hypoperfusion rats, which indicates that simvastatin may be used as an adjunctive drug to improve the prognosis of patients with vascular cognitive impairment and dementia.

Key words: simvastatin, chronic cerebral hypoperfusion, post-synaptic density 95, synaptophysin, vascular cognitive impairment, dementia

CLC Number:

Mou Zichao, Wang Dan, Wang Xiaoyan, Li Siyu, Wang Zhiqiang, Wang Qingsong.

Oral simvastatin for 3 continuous months improves learning and memory ability of chronic cerebral hypoperfusion rats [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(26): 4190-4195.

Figures/Tables 5

References

[1] ZHOU M, WANG H, ZENG X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet.2019;394(10204): 1145-1158.

[2] VÖLGYI K, GULYÁSSY P, TODOROV MI, et al. Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex. Mol Neurobiol.2018;55(5):4253-4266.

[3] LIANG S, ZHANG J, ZHANG Q, et al. Longitudinal tracing of white matter integrity on diffusion tensor imaging in the chronic cerebral ischemia and acute cerebral ischemia. Brain Res Bull. 2019;154:135-141.

[4] CORRIVEAU RA, BOSETTI F, EMR M, et al. The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline. Cell Mol Neurobiol.2016;36(2):281-288.

[5] APPLETON JP, SCUTT P, SPRIGG N, et al. Hypercholesterolaemia and vascular dementia. Clin Sci (Lond).2017;131(14):1561-1578.

[6] TRIGIANI LJ, ROYEA J, TONG XK, et al. Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia. FASEB J 2019;33(12):13280-13293.

[7] FANG SC, XIE H, CHEN F, et al.Simvastatin ameliorates memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Neuroscience. 2017;355:200-211.

[8] CHAN D, BINKS S, NICHOLAS JM, et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol.2017;16(8):591-600.

[9] SWIGER KJ, MANALAC RJ, BLUMENTHAL RS, et al.Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc.2013;88(11):1213-1221.

[10] MCGUINNESS B, CRAIG D, BULLOCK R, et al.Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;(1): CD003160.

[11] BHUVANENDRAN S, BAKAR SNS, KUMARI Y, et al. Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion. Sci Rep. 2019;9(1):14507.

[12] HE J, HUANG Y, DU G, et al. Lasting spatial learning and memory deficits following chronic cerebral hypoperfusion are associated with hippocampal mitochondrial aging in rats. Neuroscience. 2019;415: 215-229.

[13] FARKAS E, LUITEN PG, BARI F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion- related neurodegenerative diseases. Brain Res Rev. 2007;54(1): 162-180.

[14] ANISIMOVA AV, GUNCHENKO AS, IKONNIKOVA AY, et al. A clinical and genetic analysis of risk factors for the development of acute and chronic cerebral ischemia. Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(3. Vyp. 2):62-67.

[15] DUNCOMBE J, KITAMURA A, HASE Y, et al. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Clin Sci (Lond).2017;131(19):2451-2468.

[16] 何婧,黄燕,杜果,等.慢性脑低灌注致模型大鼠学习记忆受损及海马α-突触核蛋白变化[J].中国组织工程研究,2018,22(20):3230-3236.

[17] WANG Z, FAN J, WANG J, et al. Chronic cerebral hypoperfusion induces long-lasting cognitive deficits accompanied by long-term hippocampal silent synapses increase in rats. Behav Brain Res. 2016; 301:243-252.

[18] KOLOS YA, GRIGORIYEV IP, KORZHEVSKYI DE. A synaptic marker synaptophysin. Morfologiia. 2015;147(1):78-82.

[19] FUNK AJ, MIELNIK CA, KOENE R, et al. Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia. Schizophr Bull.2017;43(4): 891-899.

[20] DU SQ, WANG XR, XIAO LY, et al. Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion? Mol Neurobiol. 2017;54(5):3670-3682.

[21] CHU CS, TSENG PT, STUBBS B, et al. Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis. Sci Rep.2018;8(1):5804.

[22] BUNT CW, HOGAN AJ. The Effect of Statins on Dementia and Cognitive Decline. Am Fam Physician.2017;95(3):151-152.

[23] GEIFMAN N, BRINTON RD, KENNEDY RE, et al. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer's disease. Alzheimers Res Ther.2017;9(1):10.

[24] RICHARDSON K, SCHOEN M, FRENCH B, et al. Statins and cognitive function: a systematic review. Ann Intern Med.2013;159(10): 688-697.

[25] SCHULTZ BG, PATTEN DK, BERLAU DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener.2018;7:5.

[26] CHATTERJEE S1, KRISHNAMOORTHY P, RANJAN P, et al. Statins and cognitive function: an updated review. Curr Cardiol Rep. 2015; 17(2):4.

[27] LI R, WANG TJ, LYU PY, et al. Effects of Plasma Lipids and Statins on Cognitive Function. Chin Med J (Engl). 2018;131(4):471-476.

[28] JALAL FY, YANG Y, THOMPSON JF, et al. Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP.J Cereb Blood Flow Metab.2015;35(7):1145-1153.

[29] REUTER B, RODEMER C, GRUDZENSKI S, et al. Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke. Transl Stroke Res.2015;6(2):156-159.

[30] CARVALHO K, FAIVRE E, PIETROWSKI MJ, et al. Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor. Brain. 2019;142(11): 3636-3654.

[31] STIVAROS S,GARG S, TZIRAKI M, et al. Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA). Mol Autism.2018;9:12.