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Decreased Levels of Active Upa and KLK8 Assessed by [ In FULL-LENGTH ORIGINAL RESEARCH Decreased levels of active uPA and KLK8 assessed by [111In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy *Stephan Missault, *†Lore Peeters, *Halima Amhaoul, ‡§David Thomae, *Annemie Van Eetveldt, *Barbara Favier, *Anagha Thakur, §Jeroen Van Soom, ¶Asla Pitkanen,€ §Koen Augustyns, §Jurgen Joossens, ‡Steven Staelens, and *1Stefanie Dedeurwaerdere Epilepsia, 58(9):1615–1625, 2017 doi: 10.1111/epi.13845 SUMMARY Objective: Urokinase-type plasminogen activator (uPA) and kallikrein-related pepti- dase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [111In] MICA-401. As the first step in exploring the applicability of [111In]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [111In]MICA-401 distribution in the brain in two animal mod- els: kainic acid–induced status epilepticus (KASE) and controlled cortical impact (CCI)–induced traumatic brain injury (TBI). Methods: In the KASE model, in vitro autoradiography with [111In]MICA-401 was per- formed at 7 days and 12 weeks post-SE. To assess seizure burden, rats were moni- tored using video-electroencephalography (EEG) for 1 month before the 12-week time point. In the CCI model, in vitro autoradiography was performed at 4 days and ex vivo autoradiography at 7 days post-TBI. Results: At 7 days post-SE, in vitro autoradiography revealed significantly decreased [111In]MICA-401 binding in hippocampal CA3 subfield and extrahippocampal tempo- ral lobe (ETL). In the chronic phase, when animals had developed spontaneous sei- zures, specific binding was decreased in CA3 and CA1/CA2 subfields of hippocampus, dentate gyrus, ETL, and parietal cortex. Of interest, KASE rats with the highest fre- quency of seizures had the lowest hippocampal [111In]MICA-401 binding (r = 0.76, Stephan Missault is a p ≤ 0.05). Similarly, at 4 days post-TBI, in vitro [111In]MICA-401 binding was signifi-À doctoral student at the cantly decreased in medial and lateral perilesional cortex and ipsilateral dentate gyrus. University of Antwerp. Ex vivo autoradiography at 7 days post-TBI, however, revealed increased tracer uptake in perilesional cortex and hippocampus, which was likely related to tracer leak- age due to blood–brain barrier (BBB) disruption. Significance: Strong association of reduced [111In]MICA-401 binding with seizure bur- den in the KASE model suggests that analysis of reduced levels of active uPA/KLK8 represents a novel biomarker candidate to be explored as a biomarker for epilepsy severity. However, limited BBB permeability of [111In]MICA-401 currently limits its application in vivo. Accepted June 15, 2017; Early View publication July 19, 2017. *Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium; †Bio-Imaging Lab, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; ‡Molecular Imaging Center Antwerp, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium; §Laboratory of Medicinal Chemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; and ¶Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland 1Current address: UCB Biopharma S.P.R.L., Braine-l’Alleud, Belgium. Address correspondence to Stephan Missault, Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium. E-mail: [email protected] Wiley Periodicals, Inc. © 2017 International League Against Epilepsy 1615 1616 S. Missault et al. KEY WORDS: Extracellular matrix, Urokinase-type plasminogen activator, Kallikrein-related peptidase 8, Epilepsy, Traumatic brain injury, SPECT. kallikrein-related peptidase 1 [KLK1]; hydroxynonenal, Key Points [HNE]; and acetylcholinesterase [AchE]). Recently, [111In] The radiotracer [111In]MICA-401 has a high affinity MICA-401 was evaluated for its capacity to image uPA • 6 for active urokinase-type plasminogen activator (uPA) activity in vivo by SPECT in two different cancer models. and kallikrein-related peptidases 4 and 8 (KLK4/8) Of interest, the best SPECT images were acquired at 4 days • Postmortem [111In]MICA-401 binding reveals postinjection due to a slow blood clearance of the tracer. decreased levels of active uPA/KLK8 in brain follow- Because the tracer can bind only to active enzyme, that is, ing status epilepticus and traumatic brain injury enzyme in which the catalytic site serine is available for Postmortem [111In]MICA-401 binding correlates with binding, tracer binding reflects levels of active uPA and • 6 seizure burden in a model of temporal lobe epilepsy KLK8. Little is known about the role of KLK4 in the brain; • In vivo application of [111In]MICA-401 is currently therefore we limit the interpretation of the results to uPA limited due to its incapacity to cross the intact blood– and KLK8. brain barrier The present study was designed to evaluate the capacity of [111In]MICA-401 to image the spatiotemporal dynamics of active uPA and KLK8 in the brain in the following two Epilepsy affects approximately 69 million people world- rodent models of acquired epilepsy: the kainic acid–induced wide.1 Despite >20 antiepileptic drugs on the market, 30% status epilepticus (KASE) model of mesial temporal lobe of patients remain in unsatisfactory seizure control.2 There- epilepsy (TLE) and the controlled cortical impact (CCI) fore, identification of epileptogenic mechanisms remains a model of posttraumatic epilepsy. Our in vitro data show a 111 major unmet need in neurology. reduction in [ In]MICA-401 binding in several injured Studies over the past 10 years have revealed involvement brain areas during the first postinjury week in both models, of extracellular proteases in the pathogenesis of epilepsy (re- which is even more pronounced and widespread in the viewed in Lukasiuk et al.3 and Pitkanen et al.4). These pro- chronic phase in the KASE model, when spontaneous sei- teases degrade various components of the extracellular zures have developed. Moreover, the reduced hippocampal 111 matrix, facilitating plasticity in both physiologic and patho- binding of [ In]MICA-401 correlated with the seizure bur- logic conditions. One family of extracellular proteases are den. serine proteases, which include urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8), Methods also known as neuropsin or brain serine protease 1 (BSP1).5 Because these enzymes are located extracellularly, assess- Study design ment of their activity in vivo would provide an attractive tool Study design is shown in Figure 1. for monitoring the progression of extracellular plasticity. Our research group has recently reported the synthesis of a Animals novel activity-based single-photon emission computed Fifty-four male Sprague-Dawley rats were purchased tomography (SPECT) probe, [111In]MICA-401.6 The probe from Harlan Laboratories, the Netherlands. Upon arrival, was designed based on a diphenyl phosphonate scaffold, animals were single housed in a temperature- and humidity- which binds covalently to the alcohol group of the active site controlled environment on a 12 h light–dark cycle with serine of serine proteases. It also bears a benzyl guanidine standard food and water available ad libitum. Animals were moiety, which provides a high selectivity toward uPA,7 treated in accordance with the guidelines approved by the KLK8, and KLK4, and a polyethylene glycol (PEG) linker to European Ethics Committee (decree 2010/63/EU) and the connect the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraa- Animal Welfare Act (7 USC 2131). Animal experiments cetic acid (DOTA)-chelator, which is used as a complexing were approved by the ethical committee of the University of agent for radioisotope indium-111 (111In). In vitro evaluation Antwerp, Belgium (ECD 2012-62). of the binding kinetics of [111In]MICA-401 revealed that the probe was highly selective toward uPA, KLK8, and KLK4 Kainic acid–induced status epilepticus (KASE) as compared to other related trypsin-like serine proteases Animals were about 8-weeks-old at the time of status (tissue-type plasminogen activator [tPA]; thrombin; plas- epilepticus (SE) induction (mean SEM weight: Æ min; Factor Xa; plasma kallikrein, plasma [KLK]; 250.9 5.2 g). The KASE model was induced as Æ Epilepsia, 58(9):1615–1625, 2017 doi: 10.1111/epi.13845 1617 uPA/KLK8 Correlate with Seizure Burden Figure 1. Study design. In vitro autoradiography (ARG) with [111In]MICA-401 was performed in rats with kainic acid–induced status epilepticus (KASE) and in rats with controlled cortical impact (CCI)–induced traumatic brain injury, and their respective controls. KASE and healthy control rats were killed at 7 days (group 1) or 12 weeks post-SE (group 2). Neuronal loss was assessed with immunohistochemistry at both time points in KASE and healthy control rats. In the 12-week KASE group, electrodes were implanted at 6 weeks post-SE and 1- month continuous video-EEG monitoring was performed between the 8th and 12th week post-SE to assess the seizure burden. In CCI- and sham-injured rats, in vitro autoradiography was done at 4 days postinjury
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