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Title
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Decreased levels of active uPA and KLK8 assessed by MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy
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Author
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Abstract
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| Objective: Urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [In-111]MICA-401. As the first step in exploring the applicability of [In-111]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [In-111]MICA-401 distribution in the brain in two animal models: 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 [In-111]MICA-401 was performed at 7 days and 12 weeks post-SE. To assess seizure burden, rats were monitored 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 [In-111]MICA-401 binding in hippocampal CA3 subfield and extrahippocampal temporal lobe (ETL). In the chronic phase, when animals had developed spontaneous seizures, 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 frequency of seizures had the lowest hippocampal [In-111]MICA-401 binding (r = -0.76, p <= 0.05). Similarly, at 4 days post-TBI, in vitro [In-111]MICA-401 binding was significantly decreased in medial and lateral perilesional cortex and ipsilateral dentate gyrus. Ex vivo autoradiography at 7 days post-TBI, however, revealed increased tracer uptake in perilesional cortex and hippocampus, which was likely related to tracer leakage due to blood-brain barrier (BBB) disruption. Significance: Strong association of reduced [In-111]MICA-401 binding with seizure burden 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 [In-111]MICA-401 currently limits its application in vivo. |
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Language
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English
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Source (journal)
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Epilepsia. - Boston, Mass.
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Publication
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Boston, Mass.
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2017
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ISSN
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0013-9580
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DOI
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10.1111/EPI.13845
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Volume/pages
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58
:9
(2017)
, p. 1615-1625
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ISI
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000409338700017
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Pubmed ID
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28722103
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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