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  • Rodent Model for Enhanced Trans-Arterial Cellular Therapy After Ischemic Stroke by Blood-Brain Barrier Modulation via Sphenopalatine Ganglion Stimulation

    Final Number:

    Michael J. Lang MD; Ruihe Lin Ph.D.; Ashwini Dayal Sharan MD; Robert H. Rosenwasser MD, FACS, FAHA; Lorraine Iacovitti Ph.D.

    Study Design:
    Laboratory Investigation

    Subject Category:
    Ischemic Stroke

    Meeting: AANS/CNS Cerebrovascular Section 2016 Annual Meeting

    Introduction: Trans-arterial administration of mesenchymal stem cells (MSCs) has been demonstrated to reduce infarct size and improve functional recovery following stroke. We tested the hypothesis that reversible opening of the blood-brain barrier (BBB) by sphenopalatine ganglion (SPG) stimulation enhances graft survival and recovery.

    Methods: Sprague-Dawley rats (n=30) underwent induced ischemia by middle cerebral artery occlusion (MCAO). The negative control group (n=6) underwent MCAO alone. Twenty-four hours following MCAO, remaining animals were injected with 1x106 male rat MSCs into the ipsilateral internal carotid artery. Cells were cultured from bone marrow of transgenic S-D rats with germline expression of green fluorescent protein (GFP+). Positive controls (n=12) underwent MSC infusion alone. Immediately prior to MSC infusion, the experimental group (n=12) underwent bipolar stimulation of postganglionic parasympathetic fibers of the SPG within the orbit to selectively open the ipsilateral BBB.

    Results: : Rats underwent functional testing until post-stroke day 14 and were subsequently sacrificed. Direct fluorescence of GFP+ cells and enhanced immunofluorescence with anti-GFP was used to track infused cells. Functional testing (including modified neurologic severity score), infarct volume, and histologic differentiation of MSCs into glial, neuronal and microglial phenotypes co-localizing with GFP positivity between each of three groups will be presented.

    Conclusions: Early results suggest SPG stimulation-mediated BBB modulation may enhance the graft yield of trans-arterial cellular therapy. The future implications of SPG stimulation for blood-brain barrier modulation in the setting of cellular therapy will also be discussed.

    Patient Care: This model for BBB modulation offers substantial potential for drug and cellular therapy in combination with the selectivity of endovascular delivery.

    Learning Objectives: Discuss BBB modulation as a potential modality for enhanced trans-arterial delivery by sphenopalatine ganglion stimulation.

    References: 1. Khurana D, Kaul S, Bornstein NM, Group IS: Implant for augmentation of cerebral blood flow trial 1: a pilot study evaluating the safety and effectiveness of the Ischaemic Stroke System for treatment of acute ischaemic stroke. Journal of Stroke 4:1–6, 2009 2. Liu L, Eckert MA, Riazifar H, Kang D-K, Agalliu D, Zhao W: From Blood to the Brain: Can Systemically Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier? Stem Cells International 2013:1–7, 2013 3. Shehadah A, Chen J, Kramer B, Zacharek A, Cui Y, Roberts C, et al.: Efficacy of Single and Multiple Injections of Human Umbilical Tissue-Derived Cells following Experimental Stroke in Rats. PLoS ONE 8:e54083–6, 2013 4. Suzuki N, Hardebo JE, Kahrstrom J, Owman C: Effect on cortical blood flow of electrical stimulation of trigeminal cerebrovascular nerve fibres in the rat. Acta Physiologica Scandanavia:1–10, 2007 5. Suzuki N, Hardebo JE, Owman C: Suzuki et al - Origins and Pathways of Cerebrovascular Vasoactive Intestinal Polypeptide-Positive Nerves in Rat. J Cereb Blood Flow Metab:1–16, 2010 6. Takahashi M, Zhang Z-D, Macdonald RL: Sphenopalatine ganglion stimulation for vasospasm after experimental subarachnoid hemorrhage. Journal of Neurosurgery:1–6, 2011 7. Yarnitsky D, Gross Y, Lorian A, Shalev A, Shorer S, Tanaka T, et al.: Increased BBB permeability by parasympathetic sphenopalatine ganglion stimulation in dogs. Brain Research 1018:236–240, 2004 8. Yarnitsky D, Lorian A, Shalev A, Zhang Z-D, Takahashi M, Agbaje-Williams M, et al.: Reversal of cerebral vasospasm by sphenopalatine ganglion stimulation in a dog model of subarachnoid hemorrhage. Surgical Neurology 64:5–11, 2005 9. Zhang J, Li Y, Zhang ZG, Lu M, Borneman J, Buller B, et al.: Bone marrow stromal cells increase oligodendrogenesis after stroke. J Cereb Blood Flow Metab 29:1166–1174, 2009

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