title: Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia.
abstract: The striatal-enriched phosphatase (STEP) is a component of the NMDA-receptor-mediated excitotoxic signaling pathway, which plays a key role in ischemic brain injury. Using neuronal cultures and a rat model of ischemic stroke, we show that STEP plays an initial role in neuroprotection, during the insult, by disrupting the p38 MAPK pathway. Degradation of active STEP during reperfusion precedes ischemic brain damage and is associated with secondary activation of p38 MAPK. Application of a cell-permeable STEP-derived peptide that is resistant to degradation and binds to p38 MAPK protects cultured neurons from hypoxia-reoxygenation injury and reduces ischemic brain damage when injected up to 6 h after the insult. Conversely, genetic deletion of STEP in mice leads to sustained p38 MAPK activation and exacerbates brain injury and neurological deficits after ischemia. Administration of the STEP-derived peptide at the onset of reperfusion not only prevents the sustained p38 MAPK activation but also reduces ischemic brain damage in STEP KO mice. The findings indicate a neuroprotective role of STEP and suggest a potential role of the STEP-derived peptide in stroke therapy.
authors.affiliation: Departments of Neurology and Neurosciences, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131, Yale University School of Medicine, Child Study Center, New Haven, Connecticut 06519, and Department of Neuroscience, University of Florida, Gainesville, Florida 32610.
authors.forename: Ishani
authors.initials: I
authors.lastname: Deb
authors.forename: Namratta
authors.initials: N
authors.lastname: Manhas
authors.forename: Ranjana
authors.initials: R
authors.lastname: Poddar
authors.forename: Sathyanarayanan
authors.initials: S
authors.lastname: Rajagopal
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Allan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.forename: Surojit
authors.initials: S
authors.lastname: Paul
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C489931:Ptpn5 protein, rat