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An Optimized Mouse Model for Transient Ischemic Attack

An Optimized Mouse Model for Transient Ischemic Attack. Pedrono E, Durukan A, Strbian D, Marinkovic I, Shekhar S, Pitkonen M, Abo-Ramadan U, Tatlisumak T. J Neuropathol Exp Neurol. 2010 Feb; 69(2): 188-95. 學生 : 黃怡靜 專討指導教授 : 鄭伯智 老師 林宏榮 老師. Introduction.

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An Optimized Mouse Model for Transient Ischemic Attack

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  1. An Optimized Mouse Model for Transient Ischemic Attack Pedrono E, Durukan A, Strbian D, Marinkovic I, Shekhar S, Pitkonen M, Abo-Ramadan U, Tatlisumak T. J Neuropathol Exp Neurol. 2010 Feb; 69(2): 188-95. 學生:黃怡靜 專討指導教授:鄭伯智老師林宏榮老師

  2. Introduction

  3. http://marphilback.blogspot.com/2009/05/tia-mini-strokes-and-me.htmlhttp://marphilback.blogspot.com/2009/05/tia-mini-strokes-and-me.html

  4. A transient ischemic attack (TIA) is a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction. A transient ischemic attack (TIA) is a sudden focal neurologic deficit of cerebrovascular origin lasting less than 24 hours and resolving without any residual symptoms or signs. “MRI-negative” N Engl J Med 2002; 347: 1713-16. Stroke 2008; 39: 3110-3115.

  5. Histopathology TIA  Stroke(1/3) Therapy Animal model Intraluminal suture MCAo (well-controlled reperfusion) 1. Ensures cerebral arterial occlusion and reperfusion (LDF) 2. No permanent neurological deficit at 24 hrs 3. No lesion on MRI (DWI, T2-WI) at 24 hrs

  6. Materials and Methods

  7. Adult male NMRI mice, 22-44 g. • Suture occlusion model (MCAo). • CBF - laser Doppler flowmetry (LDF). • MR imaging: • 1) 4.7 T scanner, linear birdcage RF coil. • 2) 7 coronal images, 1mm slice thickness. • 3) DWI, T2-WI. • Neurological evaluation (6-point scale of sensorimotor skills):

  8. Bregma (LDF) Journal of Cerebral Blood Flow & Metabolism (2004) 24, 668–676. Doppler shift http://bmo.tnw.utwente.nl/vinay/principle_of_laser_doppler_flowm.htm

  9. Histopathology: - hippocampus, caudoputamen, and frontoparietal cortex of both hemispheres 1) H&E stain 2) TUNEL stain (* TUNEL positivity index)

  10. Middle cerebral artery occlusion induced brain ischemic injury Ischemia-Reperfusion group (I/R) (n=6) Sham operation control group (sham) (n=4) 20min 15min *12.5min 10min 7.5min 5min 2.5min Reperfusion 24hrs Physiology parameter Sensorimotor function Histology MRI assay CBF, Tco, BW H&E stain TUNEL stain T2-WI DWI * 3 day (72 hrs) follow-up

  11. 20 min, 15 min, *12.5 min, 10 min, 7.5 min, 5 min, 2.5 min 1. Sham group 2. I/R group 1. Sensorimotor function 2. MRI assay 3. Ischemic change Ischemia-reperfusion Stabilized MCAo 0 min 24 hr * 72 hr Physiology parameters: CBF, Tco

  12. Statistical analysis: 1) Parametric data - means (± SD), unpaired t-test, 1-way analysis of variance. 2) Nonparametric data - medians, Mann-Whitney U test, Kruskal-Wallis test. 3) Spearman correlation coefficient (r). 4) p < 0.05.

  13. Results

  14.  85% 83% 96% Fig 1. Cortical cerebral blood flow (CBF) monitoring by laser Doppler flowmetry.  Successful occlusion - decrease ≧75% CBF values from the baseline. Adequate reperfusion - recovery ≧50% CBF values from the baseline after suture withdrawal.

  15. optic chiasm level hippocampal level optic chiasm level hippocampal level Fig 2. T2-weighted images at 24 hours after reperfusion.

  16. ‛ : 1 small hippocampal infarct, 2 medium-sized subcortical infarcts, 2 large confluent infarcts " : 1 small cortical infarct, 3 medium-sized cortical and subcortical infarcts ª : 1 small cortical infarct  3-day follow-up group (12.5min): no delayed change.

  17. lateral caudoputamen Ischemicchange Duration of MCAo selective neuronal necrosis (r = 0.95) pan-necrosis Fig 3. Postmortem assessments at 24 hours postreperfusion.

  18. ** p = 0.003 versus control. Fig 4. Ischemic injury parameters. (A) Assessment with H&E. • Selective neuronal necrosis (score 2) was a consistent feature in the ischemic frontoparietal cortex starting at 5 minutes of MCAo.  3-day follow-up group (12.5min): no delayed injury.

  19. ** p = 0.003 versus control. p < 0.001 Fig 4. Ischemic injury parameters. (B) Total TUNEL-positive cell counts of the right (ischemic) and left (contralateral) hemispheres. (C) Regional TUNEL counts. TUNEL positivity index Duration of MCAo (r = 0.92)  3-day follow-up group (12.5min): no delayed injury. Ann Neurol 1999;46:333-42.

  20. Conclusion

  21. MCAo of 10 minutes or less induced by the intraluminal suture method is a reliable method of inducing a mouse model of TIA.  Animal species difference ?

  22. ~ My big family ~ Thanks for Your Attention ~ .. See you ..

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