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Minimization of cerebral ischemia by collateral therapeutics
KMSA (Korea) - Konyang University, Daejeon
Department of Anatomy
Seung Yun Han, MD, PhD
Seung Yun Han, MD, PhD
Type of Research Project
- Basic science
What is the background of the project?
Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion to provide a source of residual blood flow to ischemic areas. Early cerebral collateral status is emerging as a powerful predictor of functional outcome in unselected ischemic stroke patients and in stroke patients treated with intravenous thrombolysis. Evidence from stroke patients and animal models supports the concept that collateral status in the acute phase of ischemic stroke is a major determinant of the “physiological” therapeutic time window. Therapeutic modulation of cerebral collateral flow by “collateral therapeutics” has been advocated in the acute phase of ischemic stroke but randomized preclinical or clinical studies are scarce in this field.If proved safe and effective, enhancement of collateral flow may be included in the measures of hyperacute prehospital stroke care, to be applied in the “golden hour” from symptom onset.However, no data are available to compare the efficacy and safety of collateral therapeutics with different mechanisms of action under the same conditions.
What is the aim of the project?
In the present project, we will investigate the efficacy and safety of two potent “collateral therapeutics” in rats subjected to permanent middle cerebral artery occlusion(pMCAO). The choice of the modulation strategies will be a direct donor or an indirect facilitator of nitric oxide (NO) because of their translational feasibility as emergency therapy in human ischemic stroke.
What techniques and methods are used?
In humans, the middle cerebral artery (MCA) is most commonly affected in stroke syndromes and multiple methods of MCA occlusion (MCAO) have been described to mimic this clinical syndrome in animal models.For MCAO, 1. Place rat into an induction chamber and induce anesthesia with 5% isoflurane. 2. Shave the throat and left neck region beyond the prospective incision site using clippers. 3. Apply Betadine to a gauze pad and disinfect the skin starting from the center of the surgical region, spiraling outward. Rinse with sterile gauze pad containing 70% ethanol. 4. Inject 0.2 mL of 0.5% bupivacaine subcutaneously along the prospective incision site. 5. Under an operating microscope, a ventral midline incision is performed and the superficial fascia is dissected. 6. Beneath the superficial fascia, there is glandular tissue to the left and three muscles which form a triangle: the sternohyoid, which lies midline over the trachea; the digastric (easily identified with its shiny white tendinous portion); and lastly, the sternomastoid muscle. 7. Careful sharp and blunt dissection is performed within the triangle to identify the carotid artery (exclusive blunt dissection may be preferred by some to minimize accidental tissue damage). The external, internal, and common carotid arteries (ECA, ICA, CCA) are exposed. The carotid artery is large and visibly pulses. The vagus nerve is seen coursing along the lateral aspect of both common and internal carotid arteries and is sharply dissected off the common and internal carotid arteries. 8. Two ECA branches are then dissected sharply, the first branch heading medially and the second branch heading laterally. Both branches are cauterized and cut, which allows for greater ease in mobilizing the larger vessels. 9. The ECA is now dissected more rostrally. The hyoid bone may be encountered and this will limit the extent of rostral dissection. The external carotid artery is tied off as distally as possible with a 6-0 silk suture. 10. Another 6-0 silk suture is placed loosely around the ECA near the bifurcation with the ICA. Make sure not to occlude the vessel as the intraluminal suture to be used for the occlusion will be going through here at a later step. 11. Microsurgical clips are placed on common and internal carotid arteries near the bifurcation. 12. An initial partial arteriotomyis created between the two silk suture ties on the external carotid artery. 13. Introduce a 2.2 -3.0 cm length of 4-0 monofilament nylon suture, with a kink 2.0 cm from its rounded, silicon-coated tip, into the ECA lumen down toward the CCA where the microsurgical clip is located. These sutures are commercially available (Doccol Corp., Redlands, CA, USA). Cut the remaining portion of the ECA (at the site of the partial arteriotomy) to free the stump and position the stump below the bifurcation of the ECA and ICA; this will more easily allow the intraluminal suture to slide into the ICA. 14. Tighten the silk suture around the ECA stump to secure the intraluminal nylon suture and prevent bleeding, and then remove the microvascular clip from the ICA. Open the clip slowly before removing it to check for bleeding. 15. Continue advancing the nylon suture from the ECA to ICA lumen to the middle cerebral artery (MCA). This length is typically 18-20 mm and is the reason for placing a kink in the suture prior to insertion. After a variable length of nylon suture is inserted, resistance may be felt. If this occurs with much of the nylon suture still present outside of the vessel, it indicates that the suture is likely entering the pterygopalatine artery (see note below). Pull back and curve the suture slightly to continue along the ICA, which will run more medially. Additionally, dissection of the origin of the PPA may be done to better visualize the path of the intraluminal filament. Continue to insert the nylon suture until resistance is felt at and after the 2 cm kinked position. At this point, the intraluminal suture has blocked the origin of the MCA. MCA occlusion can be confirmed by monitoring the reduction in regional cerebral blood flow using a laser Doppler flowmeter (see Materials table for one equipment source). Also note that the origin of the pterygopalatine artery off of the ICA can be directly tied off, if preferred, in order to avoid accidental intubation of this vessel with the intraluminal suture. 16. Start the timer and record occlusion start time. 17. Remove the microclip from the CCA. 18. Close the incision (dermis, panniculus carnosus, subcutaneous tissue layers) quickly with 3-0 silk suture (a simple continuous pattern will facilitate reopening for reperfusion) and carefully place the rat in a recovery cage. Check that the cage floor around the nose and mouth are free of bedding material and monitor recovery from anesthesia.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
Students participating in this research project are expected to learn to.. 1. Select the most appropriate stroke model for future study 2. Determine stroke model parameters, such as anticipated infarct size and surgical procedure 3. Determine the use of anesthetics 4. Determine the components of the inhaled gas 5. Determine the necessity and settings of intubation and ventilation 6. Set up monitoring for arterial blood pressure, blood gases, blood glucose 7. Set up temperature monitoring and maintenance 8. Set up regional cerebral blood flow monitoring 9. Determine a protocol for post-operational care 10. Determine the method and timing for infarct volume measurement 11. Determine the appropriate tests and timing for the assessment of functional deficits 12. Do a pilot study and adjust the experimental settings for further optimization 13. Assess the compliance of the trial with “Good Laboratory Practice” standards
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The professor will provide serious assistance while the student is studying. In the form of helping students, personal teaching is carried out in parallel with paper reading and lecture. In addition, if the student requires help, the professor will take part in the full experiment directly, and the whole experiment regarding the project will be supported.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report - No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
No skills needed. However, some specific knowledge is needed. 1. Subjects passed: Biology 2. Previous experience with: Laboratory
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis.ExpTher Med 2016 Nov 31;12(5):3021-3028. Epub 2016 Oct 31.
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