Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia


Cite item

Full Text

Abstract

Aim:In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models.

Background:VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear.

Objective:The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD.

Methods:The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student’s t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05.

Results:AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway.

Conclusion:This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.

About the authors

Xiuqin Li

Department of Neurology, Hebei Medical University

Email: info@benthamscience.net

Shaopeng Chen

Department of Preventive Health, Hebei General Hospital

Email: info@benthamscience.net

Guiming Zheng

Department of Rheumatology and Immunology, Hebei General Hospital

Email: info@benthamscience.net

Yanyan Yang

Department of Gynecology, Hebei General Hospital

Email: info@benthamscience.net

Nan Yin

Department of Neurology, Hebei General Hospital

Email: info@benthamscience.net

Xiaoli Niu

Department of Neurology, Hebei General Hospital

Email: info@benthamscience.net

Lixia Yao

Department of Preventive Health, Hebei General Hospital

Email: info@benthamscience.net

Peiyuan Lv

Department of Neurology, Hebei Medical University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Dichgans, M.; Leys, D. Vascular cognitive impairment. Circ. Res., 2017, 120(3), 573-591. doi: 10.1161/CIRCRESAHA.116.308426 PMID: 28154105
  2. Rincon, F.; Wright, C.B. Vascular cognitive impairment. Curr. Opin. Neurol., 2013, 26(1), 29-36. doi: 10.1097/WCO.0b013e32835c4f04
  3. Fortin, N.J.; Agster, K.L.; Eichenbaum, H.B. Critical role of the hippocampus in memory for sequences of events. Nat. Neurosci., 2002, 5(5), 458-462. doi: 10.1038/nn834 PMID: 11976705
  4. Lazarov, O.; Hollands, C. Hippocampal neurogenesis: Learning to remember. Prog. Neurobiol., 2016, 138-140, 1-18. doi: 10.1016/j.pneurobio.2015.12.006 PMID: 26855369
  5. Burke, M.J.C.; Nelson, L.; Slade, J.Y.; Oakley, A.E.; Khundakar, A.A.; Kalaria, R.N. Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias. Neuropathol. Appl. Neurobiol., 2014, 40(3), 284-295. doi: 10.1111/nan.12085 PMID: 24003901
  6. Counts, S.E.; Alldred, M.J.; Che, S.; Ginsberg, S.D.; Mufson, E.J. Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology, 2014, 79, 172-179. doi: 10.1016/j.neuropharm.2013.10.018 PMID: 24445080
  7. Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent. Med. Chem. Res., 2013, 22(11), 5324-5336. doi: 10.1007/s00044-013-0537-0
  8. Singh, R.K.; Devi, S.; Prasad, D.N. Synthesis, physicochemical and biological evaluation of 2-amino-5-chlorobenzophenone derivatives as potent skeletal muscle relaxants. Arab. J. Chem., 2015, 8(3), 307-312. doi: 10.1016/j.arabjc.2011.11.013
  9. Corsini, A.; Bellosta, S.; Baetta, R.; Fumagalli, R.; Paoletti, R.; Bernini, F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol. Ther., 1999, 84(3), 413-428. doi: 10.1016/S0163-7258(99)00045-5 PMID: 10665838
  10. Inoue, T.; Node, K. Statin therapy for vascular failure. Cardiovasc. Drugs Ther., 2007, 21(4), 281-295. doi: 10.1007/s10557-007-6038-y PMID: 17682928
  11. Zuo, Y.; Wang, Y.; Hu, H.; Cui, W. Atorvastatin protects myocardium against ischemia-reperfusion injury through inhibiting miR-199a-5p. Cell. Physiol. Biochem., 2016, 39(3), 1021-1030. doi: 10.1159/000447809 PMID: 27537066
  12. Yue, Y.H.; Bai, X.; Zhang, H.; Li, Y.; Hu, L.; Liu, L.; Mao, J.; Yang, X.; Dila, N. Gene polymorphisms affect the effectiveness of atorvastatin in treating ischemic stroke patients. Cell. Physiol. Biochem., 2016, 39(2), 630-638. doi: 10.1159/000445654 PMID: 27415775
  13. Torrandell-Haro, G.; Branigan, G.L.; Vitali, F.; Geifman, N.; Zissimopoulos, J.M.; Brinton, R.D. Statin therapy and risk of Alzheimer’s and age‐related neurodegenerative diseases. Alzheimers Dement. (N. Y.), 2020, 6(1), e12108. doi: 10.1002/trc2.12108 PMID: 33283039
  14. Schultz, B.G.; Patten, D.K.; Berlau, D.J. The role of statins in both cognitive impairment and protection against dementia: A tale of two mechanisms. Transl. Neurodegener., 2018, 7(1), 5. doi: 10.1186/s40035-018-0110-3 PMID: 29507718
  15. Wang, S.; Zhang, X.; Zhai, L.; Sheng, X.; Zheng, W.; Chu, H.; Zhang, G. Atorvastatin attenuates cognitive deficits and neuroinflammation induced by Aβ1–42 involving modulation of TLR4/TRAF6/NF-κB pathway. J. Mol. Neurosci., 2018, 64(3), 363-373. doi: 10.1007/s12031-018-1032-3 PMID: 29417448
  16. Zhao, L.; Chen, T.; Wang, C.; Li, G.; Zhi, W.; Yin, J.; Wan, Q.; Chen, L. Atorvastatin in improvement of cognitive impairments caused by amyloid β in mice: Involvement of inflammatory reaction. BMC Neurol., 2016, 16(1), 18. doi: 10.1186/s12883-016-0533-3 PMID: 26846170
  17. Sun, B.; Chen, L.; Wei, X.; Xiang, Y.; Liu, X.; Zhang, X. The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats. Biochem. Biophys. Res. Commun., 2011, 409(4), 808-813. doi: 10.1016/j.bbrc.2011.05.095 PMID: 21624354
  18. Jing, Z.; Shi, C.; Zhu, L.; Xiang, Y.; Chen, P.; Xiong, Z.; Li, W.; Ruan, Y.; Huang, L. Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J. Cereb. Blood Flow Metab., 2015, 35(8), 1249-1259. doi: 10.1038/jcbfm.2015.55 PMID: 25853908
  19. Nixon, R.A.; Yang, D.S. Autophagy and neuronal cell death in neurological disorders. Cold Spring Harb. Perspect. Biol., 2012, 4(10), a008839. doi: 10.1101/cshperspect.a008839 PMID: 22983160
  20. Son, J.H.; Shim, J.H.; Kim, K.H.; Ha, J.Y.; Han, J.Y. Neuronal autophagy and neurodegenerative diseases. Exp. Mol. Med., 2012, 44(2), 89-98. doi: 10.3858/emm.2012.44.2.031 PMID: 22257884
  21. Tung, Y.T.; Wang, B.J.; Hu, M.K.; Hsu, W.M.; Lee, H.; Huang, W.P.; Liao, Y.F. Autophagy: A double-edged sword in Alzheimer’s disease. J. Biosci., 2012, 37(1), 157-165. doi: 10.1007/s12038-011-9176-0 PMID: 22357213
  22. Xu, Z.; Wang, H.; Cui, X.; Jin, Y.; Xu, Z. Role of autophagy in myocardial reperfusion injury. Front. Biosci. (Elite Ed.), 2010, E2(3), 1147-1153. doi: 10.2741/e174 PMID: 20515786
  23. Yu, Y.; Feng, L.; Li, J.; Lan, X. A, L.; Lv, X.; Zhang, M.; Chen, L. The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits. Behav. Brain Res., 2017, 334, 155-162. doi: 10.1016/j.bbr.2017.07.003 PMID: 28688896
  24. Menzies, F.M.; Fleming, A.; Rubinsztein, D.C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci., 2015, 16(6), 345-357. doi: 10.1038/nrn3961 PMID: 25991442
  25. Mihaylova, M.M.; Shaw, R.J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol., 2011, 13(9), 1016-1023. doi: 10.1038/ncb2329 PMID: 21892142
  26. Dhiman, A.; Sharma, R.; Singh, R.K. Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021). Acta Pharm. Sin. B, 2022, 12(7), 3006-3027. doi: 10.1016/j.apsb.2022.03.021 PMID: 35865090
  27. Garza-Lombó, C.; Schroder, A.; Reyes-Reyes, E.M.; Franco, R. mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Curr. Opin. Toxicol., 2018, 8, 102-110. doi: 10.1016/j.cotox.2018.05.002 PMID: 30417160
  28. Cell culture basics https://www.vanderbilt.edu/viibre/CellCultureBasicsEU.pdf
  29. Yang, S.; Zhou, G.; Liu, H.; Zhang, B.; Li, J.; Cui, R.; Du, Y. Protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a rat model of vascular dementia. BioMed Res. Int., 2013, 2013, 1-9. doi: 10.1155/2013/215798 PMID: 24455679
  30. Zong, W.; Zeng, X.; Chen, S.; Chen, L.; Zhou, L.; Wang, X.; Gao, Q.; Zeng, G.; Hu, K.; Ouyang, D. Ginsenoside compound K attenuates cognitive deficits in vascular dementia rats by reducing the Aβ deposition. J. Pharmacol. Sci., 2019, 139(3), 223-230. doi: 10.1016/j.jphs.2019.01.013 PMID: 30799178
  31. Qian, X.; Xu, Q.; Li, G.; Bu, Y.; Sun, F.; Zhang, J. Therapeutic effect of idebenone on rats with vascular dementia via the MicroRNA-216a/RSK2/NF-κB axis. Neuropsychiatr. Dis. Treat., 2021, 17, 533-543. doi: 10.2147/NDT.S293614 PMID: 33628024
  32. Luca, M.; Luca, A.; Calandra, C. The role of oxidative damage in the pathogenesis and progression of alzheimer’s disease and vascular dementia. Oxid. Med. Cell. Longev., 2015, 2015, 1-8. doi: 10.1155/2015/504678 PMID: 26301043
  33. Zhang, L.; Fang, Y.; Cheng, X.; Lian, Y.; Xu, H.; Zeng, Z.; Zhu, H. TRPML1 participates in the progression of alzheimer’s disease by regulating the PPARγ/AMPK/Mtor signalling pathway. Cell. Physiol. Biochem., 2017, 43(6), 2446-2456. doi: 10.1159/000484449 PMID: 29131026
  34. Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and in vitro cytotoxicity study of benzodiazepine-mustard conjugates as potential brain anticancer agents. J. Saudi Chem. Soc., 2017, 21(Suppl. 1), S86-S93. doi: 10.1016/j.jscs.2013.10.004
  35. Li, X.; Xiao, H.; Lin, C.; Sun, W.; Wu, T.; Wang, J.; Chen, B.; Chen, X.; Cheng, D. Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis. Int. J. Nanomedicine, 2019, 14, 649-665. doi: 10.2147/IJN.S189819 PMID: 30697048
  36. Wei, C.; Xu, X.; Zhu, H.; Zhang, X.; Gao, Z. Promotive role of microRNA 150 in hippocampal neurons apoptosis in vascular dementia model rats. Mol. Med. Rep., 2021, 23(4), 257. doi: 10.3892/mmr.2021.11896 PMID: 33576461
  37. Tian, Z.; Ji, X.; Liu, J. Neuroinflammation in vascular cognitive impairment and dementia: Current evidence, advances, and prospects. Int. J. Mol. Sci., 2022, 23(11), 6224. doi: 10.3390/ijms23116224 PMID: 35682903
  38. Ni, M.; Zhang, J.; Huang, L.; Liu, G.; Li, Q. A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex. J. Pharmacol. Sci., 2018, 138(2), 107-115. doi: 10.1016/j.jphs.2018.08.012 PMID: 30366873
  39. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol., 2011, 13(2), 132-141. doi: 10.1038/ncb2152 PMID: 21258367
  40. Alers, S.; Löffler, A.S.; Wesselborg, S.; Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Cross talk, shortcuts, and feedbacks. Mol. Cell. Biol., 2012, 32(1), 2-11. doi: 10.1128/MCB.06159-11 PMID: 22025673
  41. Shinojima, N.; Yokoyama, T.; Kondo, Y.; Kondo, S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy, 2007, 3(6), 635-637. doi: 10.4161/auto.4916 PMID: 17786026

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers