Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities

Abstract

OBJECTIVE 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.

Neurovascular Unit Protection From Cerebral Ischemia–Reperfusion Injury by Radical-Containing Nanoparticles in Mice

“…The effectiveness and safety of intra-arterial neuroprotective agent or stem cell injection have been confirmed. [23][24][25] In this study, we revealed that intra-arterial RNP treatment protected neuronal cells and the BBB from reperfusion damage.…”

Intra-arterial neuroprotective therapy as an adjunct to endovascular intervention in acute ischemic stroke: A review of the literature and future directions

“…51 Khan et al administered 0.5 mg/kg of NCTD dissolved in dimethyl sulfoxide and diluted in normal saline (ratio of 1:5) into the ICA of spontaneously hypertensive rats immediately following 90 min of MCAo at a rate of 0.10 ml/min over 5-7 min. 52 Neurological assessment was performed using the ladder rung walking test at days 1, 3, and 7 following stroke, and also daily using the Garcia Neurological Test. MRI was performed at 24 h to assess infarct volumes and blood brain barrier integrity.…”

Hypothermia and brain inflammation after cardiac arrest

“…[ 83 ] Decreased MMP-9 activity has been shown to be protective against acute injury. [ 84 85 86 87 88 ] However, interventions affecting MMPs need to be approached carefully given that their activity is presumed to be protective during the recovery phase. [ 89 ] Anti-inflammatory mediators have also been investigated for treatment of I/R injury.…”