title: Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities.
abstract: OBJECT Matrix metalloprotease-9 (MMP-9) plays a critical role in infarct progression, blood-brain barrier (BBB) disruption, and vasogenic edema. While systemic administration of MMP-9 inhibitors has shown neuroprotective promise in ischemic stroke, there has been little effort to incorporate these drugs into endovascular modalities. By modifying the rodent middle cerebral artery occlusion (MCAO) model to allow local intraarterial delivery of drugs, one has the ability to mimic endovascular delivery of therapeutics. Using this model, the authors sought to maximize the protective potential of MMP-9 inhibition by intraarterial administration of an MMP-9 inhibitor, norcantharidin (NCTD). METHODS Spontaneously hypertensive rats were subjected to 90-minute MCAO followed immediately by local intraarterial administration of NCTD. The rats' neurobehavioral performances were scored according to the ladder rung walking test results and the Garcia neurological test for as long as 7 days after stroke. MRI was also conducted 24 hours after the stroke to assess infarct volume and BBB disruption. At the end of the experimental protocol, rat brains were used for active MMP-9 immunohistochemical analysis to assess the degree of MMP-9 inhibition. RESULTS NCTD-treated rats showed significantly better neurobehavioral scores for all days tested. MR images also depicted significantly decreased infarct volumes and BBB disruption 24 hours after stroke. Inhibition of MMP-9 expression in the ischemic region was depicted on immunohistochemical analysis, wherein treated rats showed decreased active MMP-9 staining compared with controls. CONCLUSIONS Intraarterial NCTD significantly improved outcome when administered at the time of reperfusion in a spontaneously hypertensive rat stroke model. This study suggests that supplementing endovascular revascularization with local neuroprotective drug therapy may be a viable therapeutic strategy.
authors.affiliation: J.B. Marshall Laboratory for Neurovascular Therapeutics at Dartmouth;|Division of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire;
authors.forename: Imad S
authors.initials: IS
authors.lastname: Khan
authors.affiliation: Department of Neurosurgery, Vanderbilt University Medical Center;
authors.forename: Mitchell
authors.initials: M
authors.lastname: Odom
authors.affiliation: Department of Neurosurgery, Vanderbilt University Medical Center;
authors.forename: Moneeb
authors.initials: M
authors.lastname: Ehtesham
authors.affiliation: Vanderbilt University Institute of Imaging Sciences; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Colvin
authors.affiliation: Vanderbilt University Institute of Imaging Sciences; and.
authors.forename: C Chad
authors.initials: CC
authors.lastname: Quarles
authors.affiliation: Department of Neurology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: BethAnn
authors.initials: B
authors.lastname: McLaughlin
authors.affiliation: J.B. Marshall Laboratory for Neurovascular Therapeutics at Dartmouth;|Division of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Singer
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007269:Injections, Intra-Arterial; D008297:Male; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D061965:Matrix Metalloproteinase Inhibitors; C069741:norcantharidin; D020780:Matrix Metalloproteinase 9
keywords: BBB = blood-brain barrier; DMSO = dimethyl sulfoxide; ICA = internal carotid artery; IV = intravenous; MCA = middle cerebral artery; MCAO = MCA occlusion; MMP-9; MMP-9 = matrix metalloprotease-9; NCTD = norcantharidin; VEGF = vascular endothelial growth factor; intraarterial therapy; ischemia reperfusion injury; neuroprotection; norcantharidin; stroke; tPA = tissue plasminogen activator; vascular disorders