Decreased levels of active uPA and KLK 8 assessed by [ 111 In] MICA ‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Summary Objective Urokinase‐type plasminogen activator ( uPA ) and kallikrein‐related peptidase 8 ( KLK 8) are serine proteases that contribute to extracellular matrix ( ECM ) remodeling after brain injury. They can be labelled with the novel radiotracer [ 111 In] MICA ‐401. As the first step in exploring the applicability of [ 111 In] MICA ‐401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [ 111 In] 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 [ 111 In] 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 [ 111 In] MICA ‐401 binding in hippocampal CA 3 subfield and extrahippocampal temporal lobe ( ETL ). In the chronic phase, when animals had developed spontaneous seizures, specific binding was decreased in CA 3 and CA 1/ CA 2 subfields of hippocampus, dentate gyrus, ETL , and parietal cortex. Of interest, KASE rats with the highest frequency of seizures had the lowest hippocampal [ 111 In] MICA ‐401 binding ( r = −0.76, p ≤ 0.05). Similarly, at 4 days post‐ TBI , in vitro [ 111 In] 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 [ 111 In] MICA ‐401 binding with seizure burden in the KASE model suggests that analysis of reduced levels of active uPA / KLK 8 represents a novel biomarker candidate to be explored as a biomarker for epilepsy severity. However, limited BBB permeability of [ 111 In] MICA ‐401 currently limits its application in vivo.