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Neuroscience Bulletin

, Volume 34, Issue 6, pp 951–962 | Cite as

Fluoxetine is Neuroprotective in Early Brain Injury via its Anti-inflammatory and Anti-apoptotic Effects in a Rat Experimental Subarachnoid Hemorrhage Model

  • Hui-Min Hu
  • Bin Li
  • Xiao-Dong Wang
  • Yun-Shan Guo
  • Hua Hui
  • Hai-Ping Zhang
  • Biao Wang
  • Da-Geng Huang
  • Ding-Jun HaoEmail author
Original Article

Abstract

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.

Keywords

Subarachnoid hemorrhage Fluoxetine Blood-brain barrier Microglial activation Neuronal apoptosis 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81601938), the Natural Science Fund of Shaanxi Province (2016JQ8010), and the Science and Technology Projects Fund of Xi’an city (2016050SF/YX06(6)).

Compliance with Ethical Standards

Conflict of interest

All authors declare that there are no conflicts of interest.

References

  1. 1.
    Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 2014, 10: 44–58.CrossRefGoogle Scholar
  2. 2.
    Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res 2013, 4: 432–446.CrossRefGoogle Scholar
  3. 3.
    Lim CM, Kim SW, Park JY, Kim C, Yoon SH, Lee JK. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. J Neurosci Res 2009, 87: 1037–1045.CrossRefGoogle Scholar
  4. 4.
    Lee JY, Lee HE, Kang SR, Choi HY, Ryu JH, Yune TY. Fluoxetine inhibits transient global ischemia-induced hippocampal neuronal death and memory impairment by preventing blood-brain barrier disruption. Neuropharmacology 2014, 79: 161–171.CrossRefGoogle Scholar
  5. 5.
    Lee JY, Kim HS, Choi HY, Oh TH, Yune TY. Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain 2012, 135: 2375–2389.CrossRefGoogle Scholar
  6. 6.
    Lee JY, Kang SR, Yune TY. Fluoxetine prevents oligodendrocyte cell death by inhibiting microglia activation after spinal cord injury. J Neurotrauma 2015, 32: 633–644.CrossRefGoogle Scholar
  7. 7.
    Wang Y, Neumann M, Hansen K, Hong SM, Kim S, Noble-Haeusslein LJ, et al. Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury. J Neurotrauma 2011, 28: 259–268.CrossRefGoogle Scholar
  8. 8.
    Marquez-Romero JM, Arauz A, Ruiz-Sandoval JL, Cruz-Estrada Ede L, Huerta-Franco MR, Aguayo-Leytte G, et al. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial. Trials 2013, 14: 77.CrossRefGoogle Scholar
  9. 9.
    Li JR, Xu HZ, Nie S, Peng YC, Fan LF, Wang ZJ, et al. Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subrachnoid hemorrhage in rats. J Neuroinflammation 2017, 14: 186.CrossRefGoogle Scholar
  10. 10.
    Sugawara T, Ayer R, Jadhav V, Zhang JH. A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 2008, 167: 327–334.CrossRefGoogle Scholar
  11. 11.
    Li Z, You Z, Li M, Pang L, Cheng J, Wang L. Protective effect of resveratrol on the brain in a rat model of epilepsy. Neurosci Bull 2017, 33: 273–280.CrossRefGoogle Scholar
  12. 12.
    Zhang ZY, Sun BL, Liu JK, Yang MF, Li DW, Fang J, et al. Activation of mGluR5 attenuates microglial activation and neuronal apoptosis in early brain injury after experimental subarachnoid hemorrhage in rats. Neurochem Res 2015, 40: 1121–1132.CrossRefGoogle Scholar
  13. 13.
    Li D, Zhang L, Huang X, Liu L, He Y, Xu L, et al. WIP1 Phosphatase plays a critical neuroprotective role in brain injury induced by high-altitude hypoxic inflammation. Neurosci Bull 2017, 33: 292–298.CrossRefGoogle Scholar
  14. 14.
    Kooijman E, Nijboer CH, van Velthoven CT, Mol W, Dijkhuizen RM, Kesecioglu J, et al. Long-term functional consequences and ongoing cerebral inflammation after subarachnoid hemorrhage in the rat. PLoS One 2014, 9: e90584.CrossRefGoogle Scholar
  15. 15.
    Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke 2002, 33: 1225–1232.CrossRefGoogle Scholar
  16. 16.
    Zhang ZY, Jiang M, Fang J, Yang MF, Zhang S, Yin YX, et al. Enhanced therapeutic potential of nano-curcumin against subarachnoid hemorrhage-induced blood-brain barrier disruption through inhibition of inflammatory response and oxidative stress. Mol Neurobiol 2017, 54: 1–14.CrossRefGoogle Scholar
  17. 17.
    Hanafy KA. The role of microglia and the TLR4 pathway in neuronal apoptosis and vasospasm after subarachnoid hemorrhage. J Neuroinflammation 2013, 10: 83.CrossRefGoogle Scholar
  18. 18.
    Sehba FA, Hou J, Pluta RM, Zhang JH. The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol 2012, 97: 14–37.CrossRefGoogle Scholar
  19. 19.
    Caiaffo V, Oliveira BD, de Sa FB, Evencio Neto J. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacol Res Perspect 2016, 4: e00231.CrossRefGoogle Scholar
  20. 20.
    Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A. Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology 2011, 61: 592–599.CrossRefGoogle Scholar
  21. 21.
    Zhang F, Zhou H, Wilson BC, Shi JS, Hong JS, Gao HM. Fluoxetine protects neurons against microglial activation-mediated neurotoxicity. Parkinsonism Relat Disord 2012, 18 Suppl 1: S213–217.CrossRefGoogle Scholar
  22. 22.
    Cai J, Cao S, Chen J, Yan F, Chen G, Dai Y. Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model. Neurosci Lett 2015, 600: 238–243.CrossRefGoogle Scholar
  23. 23.
    Dong YS, Wang JL, Feng DY, Qin HZ, Wen H, Yin ZM, et al. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int J Med Sci 2014, 11: 282–290.CrossRefGoogle Scholar
  24. 24.
    Zhang ZY, Yang MF, Wang T, Li DW, Liu YL, Zhang JH, et al. Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. Cell Mol Neurobiol 2015, 35: 543–553.CrossRefGoogle Scholar
  25. 25.
    Fu P, Hu Q. 3,4-Dihydroxyphenylethanol alleviates early brain injury by modulating oxidative stress and Akt and nuclear factor-kappaB pathways in a rat model of subarachnoid hemorrhage. Exp Ther Med 2016, 11: 1999–2004.CrossRefGoogle Scholar
  26. 26.
    Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY, et al. Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology 2011, 60: 963–974.CrossRefGoogle Scholar
  27. 27.
    Shan H, Bian Y, Shu Z, Zhang L, Zhu J, Ding J, et al. Fluoxetine protects against IL-1beta-induced neuronal apoptosis via downregulation of p53. Neuropharmacology 2016, 107: 68–78.CrossRefGoogle Scholar
  28. 28.
    Reus GZ, Abelaira HM, Agostinho FR, Ribeiro KF, Vitto MF, Luciano TF, et al. The administration of olanzapine and fluoxetine has synergistic effects on intracellular survival pathways in the rat brain. J Psychiatr Res 2012, 46: 1029–1035.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Hui-Min Hu
    • 1
  • Bin Li
    • 2
  • Xiao-Dong Wang
    • 1
  • Yun-Shan Guo
    • 1
  • Hua Hui
    • 1
  • Hai-Ping Zhang
    • 1
  • Biao Wang
    • 1
  • Da-Geng Huang
    • 1
  • Ding-Jun Hao
    • 1
    Email author
  1. 1.Department of Spine Surgery, Honghui HospitalXi’an Jiaotong University College of MedicineXi’anChina
  2. 2.Key Laboratory of Resource Biology and Biotechnology in Western China (Ministry of Education)Northwest UniversityXi’anChina

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