Skip to main content

Advertisement

SpringerLink
Log in

Hyperlipidemia exacerbates cerebral injury through oxidative stress, inflammation and neuronal apoptosis in MCAO/reperfusion rats

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Recent studies showed that hyperglycemia enhanced brain damage when subjected to transient cerebral ischemic stroke. However, the etiologic link between them has been less known. In the present study, based on an experimental rat’s model of hyperlipidemia combined with cerebral ischemia–reperfusion injury (I/R), we herein showed that hyperlipidemia induced by high-fat diet (HFD) resulted in considerable increase in serum triglycerides, cholesterol and low-density lipoprotein cholesterol, and remarkable decrease in serum high-density lipoprotein cholesterol, which associated with an exacerbation on neurological deficit, cerebral infarct and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells in the ischemic hemisphere of cerebral I/R rats treated with HFD diet. The data showed that serum superoxide dismutase activity and glutathione peroxides content were significantly decreased, while malondialdehyde level was obviously increased by hyperlipidemia or cerebral I/R alone, especially by coexistence of hyperlipidemia and cerebral I/R; meantime, hyperlipidemia also enhanced cerebral I/R-induced protein expression of cytochrome P450 2E1 (CYP2E1) and the levels of pro-inflammatory factors tumor necrosis factor-α and IL-6 in the ischemic hemispheres. Furthermore, the combined action of hyperlipidemia and cerebral I/R resulted in a protein increase expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 compared to hyperlipidemia or cerebral I/R alone. Meanwhile, this study also showed that hyperlipidemia significantly enhanced cerebral I/R-induced transfer of cytochrome c from mitochondria to cytosolic and the protein expressions of Apaf-1 and caspase-3, but also decreased cerebral I/R-induced bcl-2 protein expression. The results reveal that hyperlipidemia exacerbates cerebral I/R-induced injury through the synergistic effect on CYP2E1 induction, which further induces reactive oxygen species formation, oxidative stress, inflammation and neuronal apoptosis by coexistence of hyperlipidemia and cerebral I/R.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Amarenco P, Rother J, Michel P, Davis SM, Donnan GA (2006) Aortic arch atheroma and the risk of stroke. Curr Atheroscler Rep 8:343–346

    Article  PubMed  Google Scholar 

  • Ansell BJ (2000) Cholesterol, stroke risk, and stroke prevention. Curr Atheroscler Rep 2:92–96

    Article  CAS  PubMed  Google Scholar 

  • Badr AE, Yin W, Mychaskiw G, Zhang JH (2001) Dual effect of HBO on cerebral infarction in MCAO rats. Am J Physiol Regul Integr Comp Physiol 280:R766–R770

    CAS  PubMed  Google Scholar 

  • Becker KJ (2001) Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol 14(3):349–353

    Article  CAS  PubMed  Google Scholar 

  • Cai Q, Wei H (1996) Effect of dietary genistein on antioxidant enzyme activities in SENCAR mice. Nutr Cancer 25:1–7

    Article  CAS  PubMed  Google Scholar 

  • Cederbaum AI, Wu D, Mari M, Bai J (2001) CYP2E1-dependent toxicity and oxidative stress in HepG2 cells. Free Radic Biol Med 31:1539–1543

    Article  CAS  PubMed  Google Scholar 

  • Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14

    Article  CAS  PubMed  Google Scholar 

  • Clemens JA (2000) Cerebral ischemia: gene activation, neuronal injury, and the protective role of antioxidants. Free Radic Biol Med 28:1526–1531

    Article  CAS  PubMed  Google Scholar 

  • Damas P, Canivet JL, de Groote D, Vrindts Y, Albert A, Franchimont P, Lamy M (1997) Sepsis and serum cytokine concentrations. Crit Care Med 25:405–412

    Article  CAS  PubMed  Google Scholar 

  • De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MJ, Shin WS, Liao JK (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68

    Article  PubMed Central  PubMed  Google Scholar 

  • Del ZG, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10:95–112

    Google Scholar 

  • Duckrow RB, Beard DC, Brennan RW (1985) Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol 17:267–272

    Article  CAS  PubMed  Google Scholar 

  • El Kossi MM, Zakhary MM (2000) Oxidative stress in the context of acute cerebrovascular stroke. Stroke 31:1889–1892

    Article  PubMed  Google Scholar 

  • Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F (2002) Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 105:2632–2637

    Article  CAS  PubMed  Google Scholar 

  • Fang X-L, Shu G, Yu J-J, Wang L-N, Yang J, Zeng Q-J, Cheng X, Zhang Z-Q, Wang S-B, Gao P, Zhu X-T, Xi QY, Zhang Y-L, Jiang Q-Y (2013) The anorexigenic effect of serotonin is mediated by the generation of NADPH oxidase-dependent ROS. PLoS One 8(1):e53142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Figueroa S, Oset-Gasque MJ, Arce C, Martinez-Honduvilla CJ, González MP (2006) Mitochondrial involvement in nitric oxide-induced cellular death in cortical neurons in culture. J Neurosci Res 83(3):441–449

    Article  CAS  PubMed  Google Scholar 

  • Gariballa SE, Hutchin TP, Sinclair AJ (2002) Antioxidant capacity after acute ischaemic stroke. QJM 95:685–690

    Article  CAS  PubMed  Google Scholar 

  • Giugliano D, Ceriello A, Paolisso G (1996) Oxidative stress and diabetic vascular complications. Diabetes Care 19:257–267

    Article  CAS  PubMed  Google Scholar 

  • Gong W-H, Zheng W-X, Wang J, Chen S-H, Pang B, Hu X-M, Cao X-L (2012) Coexistence of hyperlipidemia and acute cerebral ischemia/reperfusion induces severe liver damage in a rat model. World J Gastroenterol 18(35):4934–4943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ishikawa M, Stokes KY, Zhang JH, Nanda A, Granger DN (2004) Cerebral microvascular responses to hypercholesterolemia: roles of NADPH oxidase and P-selectin. Circ Res 94:239–244

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, Wang X (2000) Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 275(40):31199–31203

    Article  CAS  PubMed  Google Scholar 

  • Jiang YR, Miao Y, Yang L, Xue M, Guo CY, Ma XJ, Yin HJ, Shi DZ, Chen KJ (2012) Effect of chinese herbal drug-containing serum for activating-blood and dispelling-toxin on ox-LDL-induced inflammatory factors' expression in endothelial cells. Chin J Integr Med 18(1):30–33

    Article  CAS  PubMed  Google Scholar 

  • Kelicen P, Tindberg N (2004) Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta. J Biol Chem 279:15734–15742

    Article  CAS  PubMed  Google Scholar 

  • Krunkosky TM, Fischer BM, Martin LD, Jones N, Akley NJ, Adler KB (2000) Effects of TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro. Signaling pathways controlling surface and gene expression. Am J Respir Cell Mol Biol 22:685–692

    Article  CAS  PubMed  Google Scholar 

  • Lee TH, Hsu WC, Chen CJ, Chen ST (2002) Etiologic study of young ischemic stroke in Taiwan. Stroke 33:1950–1955

    Article  PubMed  Google Scholar 

  • Leppala JM, Vitim J, Fogelholm R, Albanes D, Heinonen OP (1999) Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 30:2535–2540

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Yu S, Chen Y, Wu J, Zhao J, Zhao Y (2012) Neuroprotective effects of diallyl sulfide against transient focal cerebral ischemia via anti-apoptosis in rats. Neurol Res 34(1):32–37

    Article  CAS  PubMed  Google Scholar 

  • Liu WY, He W, Li H (2013) Exhaustive training increases uncoupling protein 2 expression and decreases Bcl-2/Bax ratio in rat skeletal muscle. Oxid Med Cell Longev 2013:780719

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    Article  CAS  PubMed  Google Scholar 

  • Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

    Article  CAS  PubMed  Google Scholar 

  • Marik PE, Varon J (2001) Sepsis: state of the art. Dis Mon 47:465–532

    Article  CAS  PubMed  Google Scholar 

  • Matsuo Y, Onodera H, Shiga Y, Shozuhara H, Ninomiya M, Kihara T, Tamatani T, Miyasaka M, Kogure K (1994) Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656:344–352

    Article  CAS  PubMed  Google Scholar 

  • Meyer JS, Rogers RL, Mortel KF, Judd BW (1987) Hyperlipidemia is a risk factor for decreased cerebral perfusion and stroke. Arch Neurol 44:418–422

    Article  CAS  PubMed  Google Scholar 

  • Nita DA, Nita V, Spulber S, Moldovan M, Popa DP, Zagrean AM, Zagrean L (2001) Oxidative damage following cerebral ischemia depends on reperfusion—a biochemical study in rat. J Cell Mol Med 5:163–170

    Article  CAS  PubMed  Google Scholar 

  • Oliveira CPMS et al (2006) Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease. Braz J Med Biol Res 39:189–194

    CAS  PubMed  Google Scholar 

  • Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP (1998) The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 128:127–137

    Article  CAS  PubMed  Google Scholar 

  • Polidori MC, Mecocci P (2002) Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease. J Alzheimers Dis 4:517–522

    CAS  PubMed  Google Scholar 

  • Renton KW (2001) Alteration of drug biotransformation and elimination during infection and inflammation. Pharmacol Ther 92:147–163

    Article  CAS  PubMed  Google Scholar 

  • Sharifkazemi MB, Aslani A, Zamirian M, Moaref AR (2007) Significance of aortic atheroma in elderly patients with ischemic stroke. A hospital-based study and literature review. Clin Neurol Neurosurg 109:311–316

    Article  PubMed  Google Scholar 

  • Steinberg HO, Bayazeed B, Hook G, Johnson A, Cronin J, Baron AD (1997) Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans. Circulation 96:3287–3293

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Yang D, Kuan C (2012) Mannitol-facilitated perfusion staining with 2, 3, 5-triphenyltetrazolium chloride (TTC) for detection of experimental cerebral infarction and biochemical analysis. J Neurosci Methods 203:122–129

    Article  PubMed Central  PubMed  Google Scholar 

  • Takechi R, Galloway S, Pallebage-Gamarallage MM, Lam V, Dhaliwal SS, Mamo JC (2013) Probucol prevents blood–brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding. Clin Exp Pharmacol Physiol 40:45–52

    Article  CAS  PubMed  Google Scholar 

  • Tiku ML, Liesch JB, Robertson FM (1990) Production of hydrogen peroxide by rabbit articular chondrocytes. Enhancement by cytokines. J Immunol 145:690–696

    CAS  PubMed  Google Scholar 

  • Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP (2009) Dyslipidemia as a risk factor for ischemic stroke. Curr Top Med Chem 9:1291–1297

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Pan Y, Xue B, Wang X, Zhao F et al (2011) The antioxidative effect of electro-acupuncture in a mouse model of Parkinson's disease. PLoS One 6:e19790

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wigg AJ et al (2001) The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48:206–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yan MX, Li YQ, Meng M, Ren HB, Kou Y (2006) Long-term high-fat diet induces pancreatic injuries via pancreatic microcirculatory disturbances and oxidative stress in rats with hyperlipidemia. Biochem Biophys Res Commun 347(1):192–199

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132

    Article  CAS  PubMed  Google Scholar 

  • Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, Yamamoto M (2008) Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 13:1159–1170

    CAS  PubMed  Google Scholar 

  • Zechariah A, ElAli A, Hagemann N, Jin F, Doeppner TR, Helfrich I, Mies G, Hermann DM (2013) Hyperlipidemia attenuates vascular endothelial growth factor-induced angiogenesis, impairs cerebral blood flow, and disturbs stroke recovery via decreased pericyte coverage of brain endothelial cells. Arterioscler Thromb Vasc Biol 33(7):1561–1567

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 31171327).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Medical College of Wuhan University of Science and Technology, Wuhan, 430080, China

    Xiao-Lu Cao, Jing Du, Ying Zhang, Jing-Ting Yan & Xia-Min Hu

Authors
  1. Xiao-Lu Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing-Ting Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xia-Min Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xia-Min Hu.

Additional information

Xiao-Lu Cao and Jing Du are the co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, XL., Du, J., Zhang, Y. et al. Hyperlipidemia exacerbates cerebral injury through oxidative stress, inflammation and neuronal apoptosis in MCAO/reperfusion rats. Exp Brain Res 233, 2753–2765 (2015). https://doi.org/10.1007/s00221-015-4269-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-015-4269-x

Keywords

Search

Navigation