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Rosiglitazone Attenuates Cerebral Vasospasm and Provides Neuroprotection in an Experimental Rat Model of Subarachnoid Hemorrhage

  • Translational Research
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Abstract

Background

Glutamate and oxidative stress play important roles after subarachnoid hemorrhage (SAH). The ability to modulate glutamate transporter 1 (GLT-1) and the antioxidative effect of rosiglitazone have been demonstrated. We investigated the neuroprotective effect of rosiglitazone after SAH.

Methods

SAH was induced by double blood injection. The rats were randomly divided into sham, SAH + vehicle, and SAH + rosiglitazone groups and treated with dimethyl sulfoxide, dimethyl sulfoxide, and 6 mg/kg of rosiglitazone, respectively, at 2 and 12 h after SAH induction and then daily for 6 days. Cerebrospinal fluid dialysates were collected 30 min before SAH induction and then daily for 7 days for glutamate measurement. Mortality, body weight, and neurological scores were also measured daily. On day 7 after SAH, the wall thickness and the perimeter of the basilar artery (BA), neuron variability, GLT-1 levels, glial fibrillary acidic protein (GFAP) expression and activity, and malondialdehyde, superoxide dismutase, and catalase activities were also evaluated.

Results

Rosiglitazone improved survival (relative risk = 0.325) and neurological functions and reduced neuronal degeneration (5.7 ± 0.8 vs. 10.0 ± 0.9; P < 0.001) compared with the SAH + vehicle group. Rosiglitazone also lowered glutamate levels by 43.5-fold and upregulated GLT-1 expression by 1.5-fold and astrocyte activity by 1.8-fold compared with the SAH + vehicle group. The increase in BA wall thickness was significantly attenuated by rosiglitazone, whereas the perimeter of the BA was increased. In addition, rosiglitazone abated the 1.9-fold increase in malondialdehyde levels and the 1.6-fold increase in catalase activity after SAH.

Conclusion

Rosiglitazone reduced SAH mortality, neurological deficits, body weight loss, GFAP loss, and cerebral vasospasm by preventing the neurotoxicity induced by glutamate and oxidative stress.

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References

  1. Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006;354:387–96.

    Article  PubMed  CAS  Google Scholar 

  2. Kuo CP, Lu CH, Wen LL, et al. Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. Anesthesiology. 2011;115:1229–38.

    PubMed  CAS  Google Scholar 

  3. Wu CT, Wen LL, Wong CS, et al. Temporal changes in glutamate, glutamate transporters, basilar arteries wall thickness, and neuronal variability in an experimental rat model of subarachnoid hemorrhage. Anesth Analg. 2011;112:666–73.

    Article  PubMed  CAS  Google Scholar 

  4. Germano A, Caffo M, Angileri FF, et al. NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat. J Neurotrauma. 2007;24:732–44.

    Article  PubMed  Google Scholar 

  5. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32:1–14.

    Article  PubMed  CAS  Google Scholar 

  6. Swanson RA, Farrell K, Stein BA. Astrocyte energetics, function, and death under conditions of incomplete ischemia: a mechanism of glial death in the penumbra. Glia. 1997;21:142–53.

    Article  PubMed  CAS  Google Scholar 

  7. van Landeghem FK, Weiss T, Oehmichen M, von Deimling A. Decreased expression of glutamate transporters in astrocytes after human traumatic brain injury. J Neurotrauma. 2006;23:1518–28.

    Article  PubMed  Google Scholar 

  8. Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S. Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res Mol Brain Res. 2000;76:429–35.

    Article  PubMed  CAS  Google Scholar 

  9. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–86.

    Article  PubMed  CAS  Google Scholar 

  10. Prunell GF, Svendgaard NA, Alkass K, Mathiesen T. Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain. J Neurosurg. 2005;102:1046–54.

    Article  PubMed  Google Scholar 

  11. Sabri M, Kawashima A, Ai J, Macdonald RL. Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: a possible cause for poor prognosis. Brain Res. 2008;1238:163–71.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Murakami K, Koide M, Dumont TM, Russell SR, Tranmer BI, Wellman GC. Subarachnoid hemorrhage induces gliosis and increased expression of the pro-inflammatory cytokine high mobility group box 1 protein. Transl Stroke Res. 2011;2:72–9.

  13. Raghubir R, Verma R, Samuel SS, Raza S, Haq W, Katti SB. Anti-stroke profile of thiazolidin-4-one derivatives in focal cerebral ischemia model in rat. Chem Biol Drug Des. 2011;78:445–53.

    Article  PubMed  CAS  Google Scholar 

  14. Collino M, Aragno M, Mastrocola R, et al. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur J Pharmacol. 2006;530:70–80.

    Article  PubMed  CAS  Google Scholar 

  15. Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008;13:1813–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Wu Y, Zhao XD, Zhuang Z, et al. Peroxisome proliferator-activated receptor gamma agonist rosiglitazone attenuates oxyhemoglobin-induced Toll-like receptor 4 expression in vascular smooth muscle cells. Brain Res. 2010;1322:102–8.

    Article  PubMed  CAS  Google Scholar 

  17. Wu Y, Tang K, Huang RQ, et al. Therapeutic potential of peroxisome proliferator-activated receptor gamma agonist rosiglitazone in cerebral vasospasm after a rat experimental subarachnoid hemorrhage model. J Neurol Sci. 2011;305:85–91.

    Article  PubMed  CAS  Google Scholar 

  18. Kuo CP, Wen LL, Chen CM, et al. Attenuation of neurological injury with early baicalein treatment following subarachnoid hemorrhage in rats. J Neurosurg. 2013;119:1028–37.

    Article  PubMed  CAS  Google Scholar 

  19. Sung CS, Wen ZH, Chang WK, et al. Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res. 2004;1015:145–53.

    Article  PubMed  CAS  Google Scholar 

  20. Prunell GF, Mathiesen T, Svendgaard NA. A new experimental model in rats for study of the pathophysiology of subarachnoid hemorrhage. NeuroReport. 2002;13:2553–6.

    Article  PubMed  Google Scholar 

  21. Park S, Yamaguchi M, Zhou C, Calvert JW, Tang J, Zhang JH. Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke. 2004;35:2412–7.

    Article  PubMed  CAS  Google Scholar 

  22. Meguro T, Clower BR, Carpenter R, Parent AD, Zhang JH. Improved rat model for cerebral vasospasm studies. Neurol Res. 2001;23:761–6.

    Article  PubMed  CAS  Google Scholar 

  23. Seckin H, Yigitkanli K, Besalti O, et al. Lamotrigine attenuates cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Surg Neurol. 2008;70:344–51 (discussion 51).

    Article  PubMed  Google Scholar 

  24. Dumont AS, Dumont RJ, Chow MM, et al. Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery. 2003;53:123–33 (discussion 33-5).

    Article  PubMed  Google Scholar 

  25. Rothoerl RD, Schebesch KM, Kubitza M, Woertgen C, Brawanski A, Pina AL. ICAM-1 and VCAM-1 expression following aneurysmal subarachnoid hemorrhage and their possible role in the pathophysiology of subsequent ischemic deficits. Cerebrovasc Dis. 2006;22:143–9.

    Article  PubMed  CAS  Google Scholar 

  26. Davalos A, Castillo J, Serena J, Noya M. Duration of glutamate release after acute ischemic stroke. Stroke. 1997;28:708–10.

    Article  PubMed  CAS  Google Scholar 

  27. Nishizawa Y. Glutamate release and neuronal damage in ischemia. Life Sci. 2001;69:369–81.

    Article  PubMed  CAS  Google Scholar 

  28. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988;11:465–9.

    Article  PubMed  CAS  Google Scholar 

  29. Garcia-Bueno B, Caso JR, Perez-Nievas BG, Lorenzo P, Leza JC. Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology. 2007;32:1251–60.

    Article  PubMed  CAS  Google Scholar 

  30. Han F, Shioda N, Moriguchi S, Qin ZH, Fukunaga K. Downregulation of glutamate transporters is associated with elevation in extracellular glutamate concentration following rat microsphere embolism. Neurosci Lett. 2008;430:275–80.

    Article  PubMed  CAS  Google Scholar 

  31. Stegmayr B, Eriksson M, Asplund K. Declining mortality from subarachnoid hemorrhage: changes in incidence and case fatality from 1985 through 2000. Stroke. 2004;35:2059–63.

    Article  PubMed  Google Scholar 

  32. Law RE, Goetze S, Xi XP, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation. 2000;101:1311–8.

    Article  PubMed  CAS  Google Scholar 

  33. Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ Res. 2008;102:283–94.

    Article  PubMed  CAS  Google Scholar 

  34. Culman J, Zhao Y, Gohlke P, Herdegen T. PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol Sci. 2007;28:244–9.

    Article  PubMed  CAS  Google Scholar 

  35. Storer PD, Xu J, Chavis J, Drew PD. Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol. 2005;161:113–22.

    Article  PubMed  CAS  Google Scholar 

  36. Fatehi-Hassanabad Z, Tasker RA. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation confers functional neuroprotection in global ischemia. Neurotox Res. 2011;19:462–71.

    Article  PubMed  CAS  Google Scholar 

  37. Sullivan SM, Bjorkman ST, Miller SM, Colditz PB, Pow DV. Morphological changes in white matter astrocytes in response to hypoxia/ischemia in the neonatal pig. Brain Res. 2010;1319:164–74.

    Article  PubMed  CAS  Google Scholar 

  38. Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscientist. 2005;11:400–7.

    Article  PubMed  CAS  Google Scholar 

  39. Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia. 2005;50:427–34.

    Article  PubMed  Google Scholar 

  40. Adelson PD, Jenkins LW, Hamilton RL, Robichaud P, Tran MP, Kochanek PM. Histopathologic response of the immature rat to diffuse traumatic brain injury. J Neurotrauma. 2001;18:967–76.

    Article  PubMed  CAS  Google Scholar 

  41. Sayan-Ozacmak H, Ozacmak VH, Barut F, Jakubowska-Dogru E. Neuroprotective efficacy of the peroxisome proliferator-activated receptor-gamma ligand in chronic cerebral hypoperfusion. Curr Neurovasc Res. 2011;8:190–9.

    Article  PubMed  CAS  Google Scholar 

  42. Cowley TR, O’Sullivan J, Blau C, et al. Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP. Neurobiol Aging. 2012;33:162–75.

    Article  PubMed  CAS  Google Scholar 

  43. Yeh TH, Hwang HM, Chen JJ, Wu T, Li AH, Wang HL. Glutamate transporter function of rat hippocampal astrocytes is impaired following the global ischemia. Neurobiol Dis. 2005;18:476–83.

    Article  PubMed  CAS  Google Scholar 

  44. Chen JC, Hsu-Chou H, Lu JL, et al. Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuropharmacology. 2005;49:703–14.

    Article  PubMed  CAS  Google Scholar 

  45. Ayer RE, Zhang JH. Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl. 2008;104:33–41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Jeon H, Ai J, Sabri M, et al. Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage. BMC Neurosci. 2009;10:103.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Yi JH, Park SW, Brooks N, Lang BT, Vemuganti R. PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res. 2008;1244:164–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Luo Y, Yin W, Signore AP, et al. Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. J Neurochem. 2006;97:435–48.

    Article  PubMed  CAS  Google Scholar 

  49. Sheu WH, Chuang HC, Cheng SM, Lee MR, Chou CC, Cheng FC. Microdialysis combined blood sampling technique for the determination of rosiglitazone and glucose in brain and blood of gerbils subjected to cerebral ischemia. J Pharm Biomed Anal. 2011;54:759–64.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Meei-Shyuan Lee, PhD, Professor, School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China, for statistic consultation. The grant was supported by National Science Council (NSC 97-2314-B-016-005-MY2) and Tri-Service General Hospital (TSGH-C100-114) of Taiwan, Republic of China.

Conflict of interest

The other authors have no financial or institutional conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, #325, Section 2 Chenggung Road, Neihu 114, Taipei, Taiwan, ROC

    Bo-Feng Lin, Chan-Yang Kuo, Chun-Mei Chen, Ya-Feng Chang, Chen-Hwan Cherng & Zhi-Fu Wu

  2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC

    Bo-Feng Lin & Zhi-Fu Wu

  3. Graduate Institute of Mechanical and Electrical Engineering, National Taipei University of Technology, Taipei, Taiwan, ROC

    Chan-Yang Kuo

  4. Department of Clinical Laboratory, En Chu Kong Hospital, New Taipei City, Taiwan, ROC

    Li-Li Wen

  5. Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan, ROC

    Chih-Shung Wong

  6. Department of Cardiology, Bethany Medical Center, High Point, NC, USA

    Mei-Yu Chuang

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  1. Bo-Feng Lin
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Correspondence to Zhi-Fu Wu.

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Lin, BF., Kuo, CY., Wen, LL. et al. Rosiglitazone Attenuates Cerebral Vasospasm and Provides Neuroprotection in an Experimental Rat Model of Subarachnoid Hemorrhage. Neurocrit Care 21, 316–331 (2014). https://doi.org/10.1007/s12028-014-0010-z

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