Simvastatin improves intracerebral hemorrhage through NF‑κB‑mediated apoptosis via the MyD88/TRIF signaling pathway

Gu,Chengyao; Wu,Yunqin; Fan,Zhenyi; Han,Weiwei

doi:10.3892/etm.2017.5349

Simvastatin improves intracerebral hemorrhage through NF‑κB‑mediated apoptosis via the MyD88/TRIF signaling pathway

Authors:
- Chengyao Gu
- Yunqin Wu
- Zhenyi Fan
- Weiwei Han
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Affiliations: Department of Neurology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China, Department of Rehabilitation, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China
Published online on: October 23, 2017 https://doi.org/10.3892/etm.2017.5349
Pages: 377-382

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Abstract

The aim was to investigate the neuroprotective effects and potential mechanism mediated by simvastatin in a mouse model of intracerebral hemorrhage. CD‑1 mice were subjected to infusion of collagenase type IV into the left striatum in order to induce intracerebral hemorrhage. Western blot analysis, the TUNEL assay and the modified neurological severity score were used in the present study to analyze the efficacy of simvastatin for intracerebral hemorrhage. The results demonstrated that simvastatin treatment improved the cerebral water content and blood‑brain barrier disruption in the intracerebral hemorrhage animals. Intracerebral hemorrhage‑induced neuronal cell death was downregulated by simvastatin treatment compared with the vehicle‑treated model group. In addition, the expression levels of aquaporin‑4, matrix metallopeptidase 9 and caspase‑3 were downregulated and B‑cell lymphoma‑2 was upregulated by simvastatin treatment compared with the vehicle‑treated model. Simvastatin treatment also significantly reduced the Evans blue leakage into the injured hemispheres and improved motor function. Mechanism analysis further indicated that simvastatin treatment downregulated nuclear factor (NF)‑κB expression, and upregulated the myeloid differentiation primary response 88 (MyD88) and TIR domain‑containing adaptor protein inducing interferon‑β (TRIF) expression levels in neuronal cells in experimental mice. Furthermore, the results revealed that NF‑κB overexpression abolished the simvastatin‑downregulated MyD88 and TRIF expression levels, as well as the apoptosis of neuronal cells. In conclusion, these results indicated that simvastatin was able to attenuate brain edema and reduce cellular apoptosis by suppressing the NF‑κB‑mediated MyD88/TRIF signaling pathway subsequent to the induction of intracerebral hemorrhage in mice.

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1	Sussman ES and Connolly ES Jr: Hemorrhagic transformation: A review of the rate of hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol. 4:692013. View Article : Google Scholar : PubMed/NCBI
2	Ma B and Zhang J: Nimodipine treatment to assess a modified mouse model of intracerebral hemorrhage. Brain Res. 1078:182–188. 2006. View Article : Google Scholar : PubMed/NCBI
3	Manaenko A, Fathali N, Chen H, Suzuki H, Williams S, Zhang JH and Tang J: Heat shock protein 70 upregulation by geldanamycin reduces brain injury in a mouse model of intracerebral hemorrhage. Neurochem Int. 57:844–850. 2010. View Article : Google Scholar : PubMed/NCBI
4	Lee HJ, Kim KS, Kim EJ, Choi HB, Lee KH, Park IH, Ko Y, Jeong SW and Kim SU: Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells. 25:1204–1212. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kumar N Ganesh, Zuckerman SL, Khan IS, Dewan MC, Morone PJ and Mocco J: Treatment of intracerebral hemorrhage: A selective review and future directions. J Neurosurg Sci. 61:523–535. 2017.PubMed/NCBI
6	Lee WJ, Yeon JY, Jo KI, Kim JS and Hong SC: Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome presenting with deep intracerebral hemorrhage in young women. J Cerebrovasc Endovasc Neurosurg. 17:239–245. 2015. View Article : Google Scholar : PubMed/NCBI
7	Kanamaru K, Suzuki H and Taki W: Cerebral infarction after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl. 121:167–172. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lu L, Barfejani AH, Qin T, Dong Q, Ayata C and Waeber C: Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res. 1555:89–96. 2014. View Article : Google Scholar : PubMed/NCBI
9	Ramadan WH and Kabbara WK: Sitagliptin/simvastatin: A first combination tablet to treat type 2 diabetes and hypercholesterolemia-a review of its characteristics. Vasc Health Risk Manag. 11:125–132. 2015. View Article : Google Scholar : PubMed/NCBI
10	Taveira-DaSilva AM, Jones AM, Julien-Williams PA, Stylianou M and Moss J: Retrospective review of combined sirolimus and simvastatin therapy in lymphangioleiomyomatosis. Chest. 147:180–187. 2015. View Article : Google Scholar : PubMed/NCBI
11	Yasuda H, Yuen PS, Hu X, Zhou H and Star RA: Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int. 69:1535–1542. 2006. View Article : Google Scholar : PubMed/NCBI
12	Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, Chopp M and Seyfried DM: Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke. 40:3384–3389. 2009. View Article : Google Scholar : PubMed/NCBI
13	Lapchak PA and Han MK: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduces thrombolytic-induced intracerebral hemorrhage in embolized rabbits. Brain Res. 1303:144–150. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yang D, Knight RA, Han Y, Karki K, Zhang J, Ding C, Chopp M and Seyfried DM: Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: Magnetic resonance imaging and histological study. J Neurosurg. 114:1135–1142. 2011. View Article : Google Scholar : PubMed/NCBI
15	Shimamura N, Kakuta K, Wang L, Naraoka M, Uchida H, Wakao S, Dezawa M and Ohkuma H: Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model. Exp Brain Res. 235:565–572. 2017. View Article : Google Scholar : PubMed/NCBI
16	Park JS, Kim S, Han DK, Lee JY and Ghil SH: Isolation of neural precursor cells from skeletal muscle tissues and their differentiation into neuron-like cells. Exp Mol Med. 39:483–490. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hijioka M, Matsushita H, Hisatsune A, Isohama Y and Katsuki H: Therapeutic effect of nicotine in a mouse model of intracerebral hemorrhage. J Pharmacol Exp Ther. 338:741–749. 2011. View Article : Google Scholar : PubMed/NCBI
18	Tong LS, Shao AW, Ou YB, Guo ZN, Manaenko A, Dixon BJ, Tang J, Lou M and Zhang JH: Recombinant Gas6 augments Axl and facilitates immune restoration in an intracerebral hemorrhage mouse model. J Cereb Blood Flow Metab. 37:1971–1981. 2017. View Article : Google Scholar : PubMed/NCBI
19	Hsieh TH, Kang JW, Lai JH, Huang YZ, Rotenberg A, Chen KY, Wang JY, Chan SY, Chen SC, Chiang YH and Peng CW: Relationship of mechanical impact magnitude to neurologic dysfunction severity in a rat traumatic brain injury model. PLoS One. 12:e01781862017. View Article : Google Scholar : PubMed/NCBI
20	McGirt MJ, Pradilla G, Legnani FG, Thai QA, Recinos PF, Tamargo RJ and Clatterbuck RE: Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery. 58:945–951. 2006. View Article : Google Scholar : PubMed/NCBI
21	Sugawara T, Jadhav V, Ayer R and Zhang J: Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage. Acta Neurochir Suppl. 102:391–394. 2008. View Article : Google Scholar : PubMed/NCBI
22	Brown RJ, Epling BP, Staff I, Fortunato G, Grady JJ and McCullough LD: Polyuria and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. BMC Neurol. 15:2012015. View Article : Google Scholar : PubMed/NCBI
23	Jenson AV, Rodriguez GJ, Alvarado LA, Cruz-Flores S and Maud A: Higher rate of intracerebral hemorrhage in hispanic patients with cerebral cavernous malformation. J Vasc Interv Neurol. 8:1–4. 2015.PubMed/NCBI
24	Sugawara T, Ayer R, Jadhav V, Chen W, Tsubokawa T and Zhang JH: Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase. J Neurosci Res. 86:3635–3643. 2008. View Article : Google Scholar : PubMed/NCBI
25	Lin C, Zhao Y, Wan G, Zhu A and Wang H: Effects of simvastatin and taurine on delayed cerebral vasospasm following subarachnoid hemorrhage in rabbits. Exp Ther Med. 11:1355–1360. 2016. View Article : Google Scholar : PubMed/NCBI
26	Zhou HX, Gao LH, Meng LL, Zhang YX, Wei ZF and Si DW: Preventive and therapeutic effect of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage. Asian Pac J Trop Med. 10:152–156. 2017. View Article : Google Scholar : PubMed/NCBI
27	Zhang Z, Liu Y, Huang Q, Su Y, Zhang Y, Wang G and Li F: NF-kB activation and cell death after intracerebral hemorrhage in patients. Neurol Sci. 35:1097–1102. 2014. View Article : Google Scholar : PubMed/NCBI
28	Shen X, Ma L, Dong W, Wu Q, Gao Y, Luo C, Zhang M, Chen X and Tao L: Autophagy regulates intracerebral hemorrhage induced neural damage via apoptosis and NF-kB pathway. Neurochem Int. 96:100–112. 2016. View Article : Google Scholar : PubMed/NCBI
29	Mikael LG and Rozen R: Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-kappaB/iNOS. Cardiovasc Res. 80:151–158. 2008. View Article : Google Scholar : PubMed/NCBI