PURPOSE: To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis. MATERIALS AND METHODS: The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05. RESULTS: MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology. CONCLUSION: The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.
PURPOSE: To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis. MATERIALS AND METHODS: The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epilepticmice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05. RESULTS:MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a humanpatient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology. CONCLUSION: The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.
Authors: Rivelilson M Freitas; Silvânia M M Vasconcelos; Francisca C F Souza; Glauce S B Viana; Marta M F Fonteles Journal: FEBS J Date: 2005-03 Impact factor: 5.542
Authors: Karin Borges; Marla Gearing; Dayna L McDermott; Amy B Smith; Antoine G Almonte; Bruce H Wainer; Raymond Dingledine Journal: Exp Neurol Date: 2003-07 Impact factor: 5.330
Authors: Michael O Breckwoldt; John W Chen; Lars Stangenberg; Elena Aikawa; Elisenda Rodriguez; Shumei Qiu; Michael A Moskowitz; Ralph Weissleder Journal: Proc Natl Acad Sci U S A Date: 2008-11-14 Impact factor: 11.205
Authors: Carlos Milla; Shuxia Yang; David N Cornfield; Marie-Luise Brennan; Stanley L Hazen; Angela Panoskaltsis-Mortari; Bruce R Blazar; Imad Y Haddad Journal: Am J Physiol Lung Cell Mol Physiol Date: 2004-03-12 Impact factor: 5.464
Authors: Paolo F Fabene; Graciela Navarro Mora; Marianna Martinello; Barbara Rossi; Flavia Merigo; Linda Ottoboni; Simona Bach; Stefano Angiari; Donatella Benati; Asmaa Chakir; Lara Zanetti; Federica Schio; Antonio Osculati; Pasquina Marzola; Elena Nicolato; Jonathon W Homeister; Lijun Xia; John B Lowe; Rodger P McEver; Francesco Osculati; Andrea Sbarbati; Eugene C Butcher; Gabriela Constantin Journal: Nat Med Date: 2008-11-23 Impact factor: 53.440
Authors: Cuihua Wang; Edmund Keliher; Matthias W G Zeller; Gregory R Wojtkiewicz; Aaron D Aguirre; Leonard Buckbinder; Hye-Yeong Kim; Jianqing Chen; Kevin Maresca; Maaz S Ahmed; Negin Jalali Motlagh; Matthias Nahrendorf; John W Chen Journal: Proc Natl Acad Sci U S A Date: 2019-05-23 Impact factor: 11.205
Authors: Muhammad Ali; Giulia Fulci; Mantas Grigalavicius; Benjamin Pulli; Anning Li; Gregory R Wojtkiewicz; Cuihua Wang; Kevin Li-Chun Hsieh; Jenny J Linnoila; Theodossis A Theodossiou; John W Chen Journal: Neoplasia Date: 2022-03-02 Impact factor: 5.715