Yinian Zhang MD, PhD, Presenter: Nothing to Disclose

Daniel P. Seeburg MD, Abstract Co-Author: Nothing to Disclose

Gregory R. Wojtkiewicz MSC, Abstract Co-Author: Nothing to Disclose

Wendy Atkinson MS, Abstract Co-Author: Nothing to Disclose

Andrew Milewski, Abstract Co-Author: Nothing to Disclose

Yaqing Chen, Abstract Co-Author: Nothing to Disclose

Wei Zhang, Abstract Co-Author: Nothing to Disclose

Benjamin Pulli MD, Abstract Co-Author: Nothing to Disclose

Elisenda. Rodriguez, Abstract Co-Author: Nothing to Disclose

Ned Keliher, Abstract Co-Author: Nothing to Disclose

Filip K Swirski, Abstract Co-Author: Nothing to Disclose

John Chen MD, PhD, Abstract Co-Author: Research grant, Pfizer Inc

Increasing evidence points to a key role of inflammation in epileptogenesis. We aim to assess if an enzyme-activatable single photon emission computed tomography (SPECT) molecular agent can noninvasively track the oxidative activity of myeloperoxidase (MPO) in a murine seizure model and to study the effects of MPO inhibition during epileptogenesis.

Status epilepticus (SE) was induced in C57BL/6 mice (Charles River Lab, n=120) via i.p. injection of pilocarpine (350 mg/kg). Bis-5-hydroxytryptamide-diethylene-triamine-pentaacetate-gadolinium (bis-5HT-DTPA) was chelated to In-111, and used to sense MPO activity in vivo using SPECT-CT imaging (n=11). Western blotting and MPO assays were performed to confirm MPO protein and biological activity during acute and chronic stages. Flow cytometry was performed to determine inflammatory cell subsets involved in this process. Mice were monitored daily for 60 days after SE onset for spontaneous recurrent seizure (SRS) (n=33). Histopathological analyses for mossy fiber sprouting were performed using Timm staining at 1 month to 13 months following SE.

MPO-SPECT signal increased in pilocarpine-induced animals 24 hours after onset of SE compared to sham-induced animals (P<0.01), corresponding to elevated levels of MPO activity and protein (P <0.01). Blocking MPO activity in pilocarpine-induced animals with specific MPO inhibitor 4-aminobenzoic acid hydrazide resulted in diminished MPO-SPECT signal compared to pilocarpine-induced animals given saline (P <0.05). The duration of SRS was shortened with MPO inhibition, which also delayed the onset of SRS, and resulted in a decrease in the frequency of seizures and jerky motions. Blocking MPO activity decreased mossy fiber sprouting (P <0.01), which is a hallmark of neuronal reorganization associated with epileptogenesis.

MPO is upregulated after seizures and during epileptogenesis. Blocking MPO activity during epileptogenesis delayed the onset, ameliorated the intensity and frequency of spontaneous recurrent seizures, and inhibited mossy fiber sprouting, suggesting a role for MPO activity in epileptogenesis. Using fused SPECT-CT imaging, we non-invasively mapped elevated MPO activity during epileptogenesis in vivo, highlighting a possible role for MPO as a biomarker of epileptogenesis.

MPO could be useful as an imaging biomarker and targeted to reduce seizures.

Zhang, Y, Seeburg, D, Wojtkiewicz, G, Atkinson, W, Milewski, A, Chen, Y, Zhang, W, Pulli, B, Rodriguez, E, Keliher, N, Swirski, F, Chen, J, Myeloperoxidase Is Involved in Epileptogenesis and Can Be an Imaging Biomarker and Targeted to Reduce Seizures.  Radiological Society of North America 2011 Scientific Assembly and Annual Meeting, November 26 - December 2, 2011 ,Chicago IL. http://archive.rsna.org/2011/11034384.html