Short communication Neuroprotection for ischemic stroke in the endovascular era: A brief report on the future of intra-arterial therapy q Julius Griauzde a , Vijay M. Ravindra b , Neeraj Chaudhary a,c , Joseph J. Gemmete a,c , Aditya S. Pandey c,⇑ a Department of Radiology, University of Michigan, Ann Arbor, MI, United States b Department of Neurosurgery, Texas Children’s Hospital, Houston, TX, United States c Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States article info Article history: Received 10 June 2019 Accepted 5 August 2019 Available online xxxx Keywords: Neuroprotection Ischemic stroke Intra-arterial therapy Hypothermia Stem cells abstract Mechanical thrombectomy is now at the forefront of the treatment of large vessel acute ischemic stroke (AIS). Selective intra-arterial (IA) access has opened a new avenue for neuroprotection in AIS that has the potential to maximize local benefit while minimizing systemic effects. On a cellular level, neuro- protective strategies are aimed at reducing inflammation and free-radical formation, maintaining blood-brain barrier fidelity, and preventing cellular death. Strategies under investigation include IA infu- sion of neuroprotective agents, IA administration of stem cells, and selective IA hypothermia. In this tech- nical report, we briefly discuss pathologic mechanisms in AIS and highlight potential neuroprotective strategies that are administered selectively via the IA route. Ó 2019 Elsevier Ltd. All rights reserved. 1. Introduction Worldwide, approximately 15 million people experience an acute ischemic stroke (AIS) annually [1]. In the United States alone, one AIS is estimated to occur every 40 s [2]. Systemically adminis- tered neuroprotection in AIS has shown great promise in animal studies, but these successes have often not translated to human tri- als. With mechanical thrombectomy now at the forefront of AIS treatment, a new avenue of neuroprotection has been opened via the local intra-arterial (IA) route. IA therapies allow for selective treatment with minimization of systemic effects. In this brief report, we discuss the pathologic mechanisms of tissue injury in AIS and discuss novel strategies for IA-delivered neuroprotection. 2. Pathophysiology Cerebrovascular ischemia halts normal metabolic processes in the brain parenchyma leading to failure of Na + /K + pumps and abnormal neuronal depolarization, leading to Ca ++ influx, which activates intracellular cascades resulting in cellular dysfunction and free-radical generation [3–5]. Pathologic microvascular per- meability and disruption of the blood-brain barrier (BBB) ensues, leading to efflux of inflammatory mediators that potentiate BBB disruption, edema formation and activation of matrix metallopro- teinases (MMP) [6–11]. In cases of AIS with hemorrhagic transfor- mation, degradation of blood products leads to release of iron and oxidized free radicals, which further potentiate neuronal damage and activate pro-apoptotic cascades [12–14]. With these patho- logic mechanisms in mind, novel IA therapies aim to decrease inflammation and free-radical formation, stabilize the BBB, and regenerate irreversibly damaged cells. 3. Neuroprotective agents 3.1. Verapamil, nitroglycerin, erythropoietin, platelet-rich plasma In animal models of AIS, the calcium channel blocker verapamil has been shown to significantly decrease astrocytic inflammation and improve neuronal survival in infarcted tissue, leading to pro- found decreases in infarct volume and improved functional out- come in the treated group [15]. Subsequently, super-selective IA administration of verapamil in humans was shown to be feasible and did not increase the risk of intracranial hemorrhage or other adverse events [16]. The efficacy of IA verapamil in humans with AIS has not yet been evaluated, however. Preclinical studies of IA erythropoietin (EPO) in AIS have demonstrated neuroprotective https://doi.org/10.1016/j.jocn.2019.08.001 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved. q This study was conducted at University of Michigan Medical Center, Ann Arbor, MI. ⇑ Corresponding author at: Department of Neurosurgery, University of Michigan, 1500 E. Medical Center Drive, Room 3552 TC, Ann Arbor, MI 48109-5338, United States. E-mail addresses: jgriauz@med.umich.edu (J. Griauzde), vijay.ravindra@hsc. utah.edu (V.M. Ravindra), neerajc@med.umich.edu (N. Chaudhary), gemme- te@med.umich.edu (J.J. Gemmete), adityap@med.umich.edu (A.S. Pandey). Journal of Clinical Neuroscience xxx (xxxx) xxx Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn Please cite this article as: J. Griauzde, V. M. Ravindra, N. Chaudhary et al., Neuroprotection for ischemic stroke in the endovascular era: A brief report on the future of intra-arterial therapy, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.001