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  • Development of Neuro-Therapeutic Agents to Supplement Endovascular Revascularization in Stroke: Neuroprotection by Local Intra-Arterial (IA) Infusion of Norcantharidin in a Rodent Ischemia-Reperfusion

    Final Number:

    Imad S Khan MD; Mitchell Odom; Daniel Colvin PhD; Chad Quarles; Robert James Singer MD; Moneeb Ehtesham MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: AANS/CNS Cerebrovascular Section 2014 Annual Meeting

    Introduction: Contemporary endovascular techniques have made it possible to quickly and effectively establish reperfusion in the setting of an acute ischemic stroke (AIS). There is however a paucity of research in developing endovascular neuro-protective agents to combat the potentially devastating effects of reperfusion injury. Various studies have shown MMP-9 to be the main mediator of damage in the setting of reperfusion injury. To help develop endovascular neuro-therapeutic modalities, we tested the efficacy of IA norcantharidin (MMP-9 inhibitor) in a rodent I/R model.

    Methods: Adult spontaneously hypertensive male rats (290-310 g) underwent occlusion of their MCA for 90 minutes via an intra-luminal filament followed by local intra-arterial delivery of drug or sham treatment. Two groups of rats were investigated: treated rats (administered IA norcantharidin @ 0.5mg/kg), and control rats (administered vehicle alone). The animals were sacrificed 7 days after the stroke. Stroke volume and blood-brain-barrier disruption (BBBD) was evaluated with DWI and DCE scans, respectively. Neurological scores, foot placement accuracy and foot-fault scores (via Ladder-rung-walking test) were calculated in a blinded manner.

    Results: Rats treated with norcatharidin had significantly decreased infarct volume compared to controls (148.1 ± 10.2 vs. 178.5 ± 9.9 mm3, p<0.05, n=11 per group). Treated rats also showed significantly decreased BBBD compared to controls. This was depicted by significantly decreased percentage of regional contrast enhancement in treated rats compared to control rats (2.5 ± 0.8% vs. 0.3 ± 0.01%, p<0.05, n=5 per group). Treated rats also depicted significantly better behavioral scores (p<0.001), foot fault scores (p<0.05) and foot placement accuracy (p<0.05) for all days tested after stroke (7 days).

    Conclusions: Development of neuro-therapeutic agents to supplement revascularization techniques has the potential to significantly improve outcome in patients with AIS. Local IA norcantharidin was found to decrease the volume of infarct, decrease BBBD and improve neurological outcome in a rodent I/R model.

    Patient Care: 1. Help develop intra-arterial modalities to protect the vulnerable ischemic brain from the potentially devastating effects of reperfusion injury. 2. Provide further evidence that neuroprotective drugs administered at the time of reperfusion in stroke patients may have a significant beneficial effect.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of reperfusion injury and how it may potentially worsen clinical outcome by disrupting the blood-brain-barrier, increasing infarct volume and increasing the risk of hemorrhagic transformation. 2) Discuss, in small groups about how matrix metalloproteinase (especially MMP-9) play an important part in reperfusion injury after ischemic episode, and systemically administered MMP-9 inhibitors have been shown to decrease reperfusion injury in various stroke models 3) Identify potentially effective supplemental endovascular treatment to provide neuroprotection to the ischemic brain from reperfusion injury: MMP-9 inhibitors administered once locally (intra-arterially) at the time of reperfusion in a rodent model have a significant neuroprotective effect.

    References: 1. Chen Y-J, Chang W-M, Liu Y-W, Lee C-Y, Jang Y-H, Kuo C-D, et al. A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells. Chem Biol Interact. 2009 Oct 30;181(3):440–6. 2. Dang S, Liu X, Fu P, Gong W, Yan F, Han P, et al. Neuroprotection by local intra-arterial infusion of erythropoietin after focal cerebral ischemia in rats. Neurol Res. 2011 Jun;33(5):520–8. 3. Dejonckheere E, Vandenbroucke RE, Libert C. Matrix metalloproteinases as drug targets in ischemia/reperfusion injury. Drug Discov Today. 2011 Sep;16(17-18):762–78. 4. Marinov MB, Harbaugh KS, Hoopes PJ, Pikus HJ, Harbaugh RE. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. J Neurosurg. 1996 Jul;85(1):117–24. 5. Morancho A, Rosell A, García-Bonilla L, Montaner J. Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? Ann N Y Acad Sci. 2010 Oct;1207:123–33. 6. Saver JL. Improving reperfusion therapy for acute ischaemic stroke. J Thromb Haemost JTH. 2011 Jul;9 Suppl 1:333–43. 7. Yeh C-B, Hsieh M-J, Hsieh Y-H, Chien M-H, Chiou H-L, Yang S-F. Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity. PloS One. 2012;7(2):e31055.

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