Neurological Sciences

, Volume 35, Issue 8, pp 1203–1208

Expression of HIF-1α and MDR1/P-glycoprotein in refractory mesial temporal lobe epilepsy patients and pharmacoresistant temporal lobe epilepsy rat model kindled by coriaria lactone

Original Article


Hypoxia-inducible factor-1α (HIF-1α) is thought to mediate pharmacoresistance in tumor by inducing Pgp overexpression. We aimed to investigate the expression of HIF-1α and MDR1/P-glycoprotein in refractory epilepsy, to explore the correlation of HIF-1α with epilepsy multidrug resistance. We collected hippocampus and mesial temporal lobe (MTL) cortex of refractory mesial temporal lobe epilepsy (mTLE) patients that underwent surgery, and established a pharmacoresistant TLE rat model kindled by coriaria lactone. We used real-time quantitative PCR (RQ-PCR) and western blot to investigate expression of HIF-1α and MDR1 in hippocampus and MTL/entorhinal cortex. We found that the expression of HIF-1α and MDR1, at both mRNA and protein levels, were up-regulated in hippocampus and MTL cortex of mTLE patients compared with the control cortex (all P < 0.05), and increased in hippocampus and entorhinal cortex of kindled rat model versus the control group (all P < 0.05). These results demonstrated the overexpression of HIF-1α and MDR1/Pgp in hippocampus and MTL/entorhinal cortex of mTLE patients and the pharmacoresistant TLE rat model. HIF-1α may have a regulatory effect on MDR1 expression in refractory epilepsy, which is probably consistent with MDR mechanism in tumor.


HIF-1α Pgp Multidrug resistance mTLE Epilepsy rat model Coriaria lactone 


  1. 1.
    Brandt C, Bethmann K, Gastens AM et al (2006) The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis 24(1):202–211PubMedCrossRefGoogle Scholar
  2. 2.
    Schinkel AH (1999) P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36(2–3):179–194PubMedCrossRefGoogle Scholar
  3. 3.
    Sisodiya SM, Lin WR, Harding BN et al (2002) Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125(Pt 1):22–31PubMedCrossRefGoogle Scholar
  4. 4.
    Marchi N, Hallene KL, Kight KM et al (2004) Significance of MDR1 and multiple drug resistance in refractory human epileptic brain. BMC Med 2:37PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Wu H, Hait WN, Yang JM (2003) Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res 63(7):1515–1519PubMedGoogle Scholar
  6. 6.
    Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627PubMedCrossRefGoogle Scholar
  7. 7.
    Haar CP, Hebbar P, Wallace GCt et al (2012) Drug resistance in glioblastoma: a mini review. Neurochem Res 37(6):1192–1200PubMedCrossRefGoogle Scholar
  8. 8.
    Ding Z, Yang L, Xie X et al (2010) Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol 136(11):1697–1707PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Wang GL, Jiang BH, Rue EA et al (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92(12):5510–5514PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Comerford KM, Wallace TJ, Karhausen J et al (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62(12):3387–3394PubMedGoogle Scholar
  11. 11.
    Williamson PD, French JA, Thadani VM et al (1993) Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann Neurol 34(6):781–787PubMedCrossRefGoogle Scholar
  12. 12.
    Kwan P, Arzimanoglou A, Berg AT et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51(6):1069–1077PubMedCrossRefGoogle Scholar
  13. 13.
    Wang Y, Zhou D, Wang B et al (2003) A kindling model of pharmacoresistant temporal lobe epilepsy in Sprague–Dawley rats induced by coriaria lactone and its possible mechanism. Epilepsia 44(4):475–488PubMedCrossRefGoogle Scholar
  14. 14.
    Zhou H, Tang YH, Zheng Y (2006) A new rat model of acute seizures induced by tutin. Brain Res 1092(1):207–213PubMedCrossRefGoogle Scholar
  15. 15.
    Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32(3):281–294PubMedCrossRefGoogle Scholar
  16. 16.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408PubMedCrossRefGoogle Scholar
  17. 17.
    Feldmann M, Asselin M-C, Liu J, Wang S et al (2013) P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol 12(8):777–785PubMedCrossRefGoogle Scholar
  18. 18.
    Song X, Liu X, Chi W et al (2006) Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol 58(6):776–784PubMedCrossRefGoogle Scholar
  19. 19.
    Huang LE, Gu J, Schau M et al (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin–proteasome pathway. Proc Natl Acad Sci USA 95(14):7987–7992PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Maglajlija V, Walker MC, Kovac S (2012) Severe ictal hypoxemia following focal, subclinical temporal electrographic scalp seizure activity. Epilepsy Behav 24(1):143–145PubMedCrossRefGoogle Scholar
  21. 21.
    Blum AS, Ives JR, Goldberger AL et al (2000) Oxygen desaturations triggered by partial seizures: implications for cardiopulmonary instability in epilepsy. Epilepsia 41(5):536–541PubMedCrossRefGoogle Scholar
  22. 22.
    Tae WS, Joo EY, Kim JH et al (2005) Cerebral perfusion changes in mesial temporal lobe epilepsy: SPM analysis of ictal and interictal SPECT. Neuroimage 24(1):101–110PubMedCrossRefGoogle Scholar
  23. 23.
    Oommen KJ, Saba S, Oommen JA et al (2004) The relative localizing value of interictal and immediate postictal SPECT in seizures of temporal lobe origin. J Nucl Med 45(12):2021–2025PubMedGoogle Scholar
  24. 24.
    Vielhaber S, Von Oertzen JH, Kudin AF et al (2003) Correlation of hippocampal glucose oxidation capacity and interictal FDG-PET in temporal lobe epilepsy. Epilepsia 44(2):193–199PubMedCrossRefGoogle Scholar
  25. 25.
    Matheja P, Kuwert T, Ludemann P et al (2001) Temporal hypometabolism at the onset of cryptogenic temporal lobe epilepsy. Eur J Nucl Med 28(5):625–632PubMedCrossRefGoogle Scholar
  26. 26.
    Eid T, Brines ML, Cerami A et al (2004) Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis. J Neuropathol Exp Neurol 63(1):73–83PubMedGoogle Scholar
  27. 27.
    Rigau V, Morin M, Rousset MC et al (2007) Angiogenesis is associated with blood–brain barrier permeability in temporal lobe epilepsy. Brain 130(Pt 7):1942–1956PubMedCrossRefGoogle Scholar
  28. 28.
    Chen W, Ostrowski RP, Obenaus A et al (2009) Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury. Exp Neurol 216(1):7–15PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  1. 1.Department of Neurology, West China HospitalSichuan UniversityChengduChina
  2. 2.Department of Neurosurgery, West China HospitalSichuan UniversityChengduChina

Personalised recommendations