Selective intra-arterial drug administration in a model of large vessel ischemia

Abstract

With continuing disconnect between laboratory stroke treatment models and clinical stroke therapy, we propose a novel experimental model to study stroke and vessel recanalization that mirrors acute management of large vessel stroke, with concomitant directed pharmacotherapy. Using the tandem transient ipsilateral common carotid/middle cerebral artery occlusion (MCAO) model to induce stroke in mice we then added selective intra-arterial (IA) drug administration for directed pharmacotherapy. The IA model uses micro-angio tubing placed at the bifurcation of the CCA to selectively administer the drug to the internal carotid distribution. We have shown that delivery of pharmacotherapy agents selectively through an IA injection is feasible in a mouse model, which will permit studies involving pharmacotherapy, transgenic modification, and/or a combination. Our IA model has similarities to previously published models of IA injection but differs in that we do not leave an indwelling micro-port or catheter in our animals, which is not clinically relevant as it does not reflect the human condition or current clinical management. Furthermore, we optimized our model to selectively direct therapy to the ipsilateral, stroke affected hemisphere. By developing an IA drug delivery model that mirrors clinical conditions, we are bridging the gap between basic stroke research and what is standard practice in acute ischemic stroke intervention. The IA model of drug delivery can target agents directly to the site of injury while blunting systemic effects, dose penetration issues, and administration delay that have plagued the intraperitoneal and oral drug administration models.

Matrix‐assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke‐reperfusion injury in mice

“…Wildtype C57Bl/6 mice from the Jackson laboratory (Bar Harbor, ME, USA) aged 3–4 months were used. Transient Middle Cerebral Artery Occlusion (tMCAO) was performed according to the protocols of Lee et al and Maniskas et al Briefly, the mice were anesthetized with sodium pentobarbital (65 mg/kg IP) and given an opiate, buprenorphine (0.1 mg/kg). A local analgesic, bupivacaine (0.1 mL at 0.25%), was administered at the incision site prior to surgery.…”

“…Within this work, we demonstrate the capabilities of MALDI-IMS in the direct detection of an intraperitoneally (IP)-injected small peptide, ZP1609, within intact tissue sections, and also provide visual confirmation of the successful penetration of the dipeptide across the BBB. 29 Briefly, the mice were anesthetized with sodium pentobarbital (65 mg/kg IP) and given an opiate, buprenorphine (0.1 mg/kg). A local analgesic, bupivacaine (0.1 mL at 0.25%), was administered at the incision site prior to surgery.…”

Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke

“…[15][16][17] Recently, our laboratory has published in vivo studies demonstrating the neuroprotective effects of coupling recanalization with IA verapamil in a mouse model of focal cortical ischemia (transient middle cerebral artery occlusion). 18 We demonstrated that, when administered IA following recanalization, verapamil was physiologically safe (heart rate and blood pressure), and it significantly reduced infarct volume and significantly improved functional outcome. 19 Furthermore, IA verapamil did not significantly alter post-reperfusion flow or cerebral perfusion, suggesting a therapeutic mechanism separate from its vasodilatory effects, possibly related to reduction of excitotoxic damage through its calcium channel activity.…”

“…For surviving animals, euthanasia occurred via cervical dislocation at seven days, whereupon the whole brain was removed, and either cut and stained with TTC, or flash frozen, sectioned on the cryostat (20 mm), and stained with Cresyl Violet for infarct volume using methods previously detailed. 18,19 NeuN immunohistochemistry was performed to evaluate mature neuron survival (1:1000 antibody dilution, Abcam) in the peri-infarct region. This corresponds to the cortical region that was the epicenter of the stroke morphologically identified based on cryostat sectioning to include the greatest affected area.…”

Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice

“…Mice were maintained on a 12:12 h light:dark cycle, with food and water available ad libitum. Two different stroke models were performed: transient middle cerebral artery occlusion (tMACO) [33,34] and permanent middle cerebral artery occlusion (pMCAO) [18,35]. Briefly, the mice were anesthetized with sodium pentobarbital (65 mg/kg i.p.)…”