Protective effects of atorvastatin on cerebral vessel autoregulation in an experimental rabbit model of subarachnoid hemorrhage

Chen,Jun‑Hui; Wu,Ting; Yang,Li‑Kun; Chen,Lei; Zhu,Jie; Li,Pei‑Pei; Hu,Xu; Wang,Yu‑Hai

doi:10.3892/mmr.2017.8074

Protective effects of atorvastatin on cerebral vessel autoregulation in an experimental rabbit model of subarachnoid hemorrhage

Authors:
- Jun‑Hui Chen
- Ting Wu
- Li‑Kun Yang
- Lei Chen
- Jie Zhu
- Pei‑Pei Li
- Xu Hu
- Yu‑Hai Wang
View Affiliations

Affiliations: Department of Neurosurgery, l0lst Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China, Department of Cardiology, l0lst Hospital of PLA, Wuxi, Jiangsu 214044, P.R. China
Published online on: November 15, 2017 https://doi.org/10.3892/mmr.2017.8074
Pages: 1651-1659
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to assess the therapeutic effects of atorvastatin on cerebral vessel autoregulation and to explore the underlying mechanisms in a rabbit model of subarachnoid hemorrhage (SAH). A total of 48 healthy male New Zealand rabbits (weight, 2‑2.5 kg) were randomly allocated into SAH, Sham or SAH + atorvastatin groups (n=16/group). The Sham group received 20 mg/kg/d saline solution, whereas 20 mg/kg/d atorvastatin was administered to rabbits in the SAH + atorvastatin group following SAH induction. Changes in diameter, perimeter and basilar artery (BA) area were assessed and expression levels of the vasoactive molecules endothelin‑1 (ET‑1), von Willebrand factor (vWF) and thrombomodulin (TM) were measured. Neuronal apoptosis was analyzed 72 h following SAH by terminal deoxynucleotidyl-transferase‑mediated dUTP nick‑end labeling (TUNEL) staining. The mortality rate in the SAH group was 18.75, 25% in the SAH + atorvastatin treated group and 0% in the Sham group (n=16/group). The neurological score in the SAH + atorvastatin group was 1.75±0.68, which was significantly higher compared with the Sham group (0.38±0.49; P<0.05). The BA area in the SAH + atorvastatin group (89.6±9.11) was significantly lower compared with the SAH group (115.4±11.0; P<0.01). The present study demonstrated that SAH induction resulted in a significant increase in the diameter, perimeter and cross‑sectional area of the BA in the SAH + atorvastatin group. Administration of atorvastatin may significantly downregulate the expression levels of ET‑1, vWF and TM (all P<0.01) vs. sham and SAH groups. TUNEL staining demonstrated that neuronal apoptosis was remarkably reduced in the hippocampus of SAH rabbits following treatment with atorvastatin (P<0.05). Atorvastatin treatment may alleviate cerebral vasospasm and mediate structural and functional remodeling of vascular endothelial cells, in addition to promoting anti‑apoptotic signaling. These results provided supporting evidence for the use of atorvastatin as an effective and well‑tolerated treatment for SAH in various clinical settings and may protect the autoregulation of cerebral vessels.

View Figures

View References

1	Komotar RJ, Schmidt JM, Starke RM, Claassen J, Wartenberg KE, Lee K, Badjatia N, Connolly ES Jr and Mayer SA: Resuscitation and critical care of poor-grade subarachnoid hemorrhage. Neurosurgery. 64:397–411. 2009. View Article : Google Scholar
2	Rosengart AJ, Schultheiss KE, Tolentino J and Macdonald RL: Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 38:2315–2321. 2007. View Article : Google Scholar
3	Steiner T, Juvela S, Unterberg A, Jung C, Forsting M and Rinkel G: European Stroke Organization: European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis. 35:93–112. 2013. View Article : Google Scholar
4	Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smirlewski P, Steiner LA and Pickard JD: Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol. 9:152–163. 2013. View Article : Google Scholar
5	Laskowitz DT and Kolls BJ: Neuroprotection in subarachnoid hemorrhage. Stroke. 41 10 Suppl:S79–S84. 2010. View Article : Google Scholar :
6	Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wangke I, Bach D, Frey A, et al: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: A randomised, double-blind, placebo-controlled phase 3 trail (CONSCIOUS-2). Lancet Neurol. 10:618–625. 2011. View Article : Google Scholar
7	Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI and Patterson JL Jr: Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 234:H371–H383. 1978.
8	Sehba FA, Pluta RM and Zhang JH: Metamorphosis of subarachnoid hemorrhage research: From delayed vasospasm to early brain injury. Mol Neurobiol. 43:27–40. 2011. View Article : Google Scholar
9	Tousoulis D, Antoniades C, Katsi V, Bosinakou E, Kotsopoulou M, Tsioufis C and Stefanadis C: The impact of early administration of low-dose atorvastatin treatment on inflammatory process, in patients with unstable angina and low cholesterol level. Int J Cardiol. 109:48–52. 2006. View Article : Google Scholar
10	Cheng G, Wei L, Zhi-Dan S, Shi-Guang Z and Xiang-Zhen L: Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci. 10:72009. View Article : Google Scholar :
11	Tseng MY, Czonsnyka M, Richards H, Pickard JD and Kirkpatrick PJ: Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation and delayed ischemic deficits after aneurismal subarachnoid hemorrhage: A phase 2 randomized placebo-controlled trial. Stroke. 36:1627–1632. 2005. View Article : Google Scholar
12	Lee YM, Chen WF, Chou DS, Jayakumar T, Hou SY, Lee JJ, Hsiao G and Sheu JR: Cyclic nucleotides and mitogen-activated protein kinase: Regulation of simvastatin in platelet. J Biomed Sci. 17:452010. View Article : Google Scholar :
13	Luzak B, Boncler M, Rywaniak J, Wilk R, Stanczyk L, Czyz M, Rysz J and Watala C: The effect of a platelet cholesterol modulation on the acetylsalicylic acid-mediated blood platelet inhibition in hypercholesterolemic patients. Eur J Pharmacol. 658:91–97. 2011. View Article : Google Scholar
14	Chen JH, Yang LK, Chen L, Wang YH, Wu Y, Jiang BJ, Zhu J and Li PP: Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. Int J Mol Med. 37:1059–1066. 2016. View Article : Google Scholar
15	Zhou C, Yamaguchi M, Kusaka G, Schonholz C, Nanda A and Zhang JH: Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage. J Cerebral Blood Flow Metab. 24:419–431. 2004. View Article : Google Scholar
16	Hu N, Wu Y, Chen BZ, Han JF and Zhou MT: Protective effect of stellate ganglion block on delayed cerebral vasospasm in an experimental rat model of subarachnoid hemorrhage. Brain Res. 1585:63–71. 2014. View Article : Google Scholar
17	Seo JH, Guo S, Lok J, Navaratna D, Whalen MJ, Kim KW and Lo EH: Neurovascular matrix metalloproteinases and the blood-brain barrier. Curr Pharm Des. 18:3645–3648. 2012. View Article : Google Scholar :
18	Zhu MX, Lu C, Xia CM, Qiao ZW and Zhu DN: Simvastatin pretreatment protects cerebrum from neuronal injury by decreasing the expressions of phosphor-CaMK II and AQP4 in ischemic stroke rats. J Mol Neurosci. 54:591–601. 2014. View Article : Google Scholar
19	Koyama Y, Maebara Y, Hayashi M, Nagae R, Tokuyama S and Michinaga S: Endothelins reciprocally regulate VEGF-A and angiopoietin-1 production in cultured rat astrocytes: Implications on astrocytic proliferation. Glia. 60:1954–1963. 2012. View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
21	Rosenberg GA and Navratil M: Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurolgy. 48:921–926. 1997. View Article : Google Scholar
22	Chang CZ, Wu SC, Kwan AL and Lin CL: Preconditioning with pitavastatin, an HMG-CoA reductase inhibitor, attenuates C-Jun N-terminal kinase activation in experimental subarachnoid hemorrhage-induced apoptosis. Acta Neurochir (Wien). 157:1031–1041. 2015. View Article : Google Scholar
23	Chou SH, Smith EE, Badjatia N, Nogueira RG, Sims JR II, Ogilvy CS, Rordorf GA and Ayata C: A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 39:2891–2893. 2008. View Article : Google Scholar
24	Wong GK, Chan DY, Siu DY, Zee BC, Poon WS, Chan MT, Gin T and Leung M: HDS-SAH Investigators: High-dose simvastatin for aneurysmal subarachnoid hemorrhage: Multicenter randomized controlled double-blinded clinical trial. Stroke. 46:382–388. 2015. View Article : Google Scholar
25	Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ and Murray GD: STASH Collaborators: Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): A multicentre randomised phase 3 trial. Lancet Neurol. 13:666–675. 2014. View Article : Google Scholar
26	Chang CZ, Wu SC, Lin CL, Hwang SL, Howng SL and Kwan AL: Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats. Acta Neurochir (Wien). 152:1399–1406. 2010. View Article : Google Scholar
27	Blann AD and Tabemer DA: A reliable marker of endothelial cell dysfunction: Does it exist. Br J Haemataol. 90:224–228. 1995.
28	Chow M, Dumont AS and Kasselletal NF: Endothelin receptor antagonists and cerebral vasospasm: An update. Neurosurgery. 51:1333–1342. 2002. View Article : Google Scholar
29	Califano F, Giovanniello T, Pantone P, Campana E, Parlapiano C, Alegiani F, Vincentelli GM and Turchetti P: Clinical importance of thrombomodulin serum levels. Eur RevMed Pharmacol Sci. 4:59–66. 2000.
30	Kästner S, Oertel MF, Scharbrodt W, Krause M, Böker DK and Deinsberger W: Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH. Acta Neurochir (Wien). 147:1271–1279. 2005. View Article : Google Scholar
31	Juvela S: Plasma endothelin concentrations after aneurysmal subarachnoid hemorrhage. J Neurosurg. 92:390–400. 2000. View Article : Google Scholar
32	Tang QF, Lu SQ, Zhao YM and Qian JX: The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage. Int J Clin Exp Med. 8:1342–1348. 2015.
33	Xu T, Zhang WG, Sun J, Zhang Y, Lu JF, Han HB, Zhou CM and Yan JH: Protective effects of thrombomodulin on microvascular permeability after subarachnoid hemorrhage in mouse model. Neuroscience. 299:18–27. 2015. View Article : Google Scholar
34	Su EJ, Geyer M, Wahl M, Mann K, Ginsburg D, Brohmann H, Petersen KU and Lawrence DA: The thrombomodulin analog Solulin promotes reperfusion and reduces infarct volume in a thrombotic stroke model. J Thromb Haemost. 9:1174–1182. 2011. View Article : Google Scholar :
35	Cahill J, Calvert JW, Marcantonio S and Zhang JH: p53 may play an orchestrating role in apoptotic cell death after experimental subarachnoid hemorrhage. Neurosurgery. 60:531–545. 2007. View Article : Google Scholar
36	Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thomberry NA, Wong WW and Yuan J: Human ICE/CED-3 protease nomenclature. Cell. 87:1711996. View Article : Google Scholar