| Biography | |
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 Prof. Keith R Pennypacker University of Kentucky, USA |
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| Title: Age-related Differences in the Response to Leukemia Inhibitory Factor after Experimental Stroke | |
| Abstract:
Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that confers neuroprotection when administered systemically after permanent middle cerebral artery (MCAO) occlusion in male three month old Sprague-Dawley rats. The neuroprotective intracellular signaling occurs through the activation of Akt kinase in both oligodendrocytes and neurons. Expression of antioxidant genes is increased in both these neural cell types; oligodendrocytes express peroxiredoxin-4 and metallothionein-3, while neurons express superoxide dismutase-3. Intravenous administration of LIF at 6, 24, and 48 post-stroke results in significantly reduced infarct volume and increased motor recovery at 72 h post-MCAO. LIF treatment ameliorated the post-stroke inflammatory response that originates in the spleen. Animals treated with LIF had a significantly smaller reduction in spleen weight and significantly lower splenic levels of the inflammatory cytokine IL-12 compared to rats treated with PBS. Furthermore, LIF also significantly reduces the number of inflammatory macrophages/microglia in the brain as measured by CD11b protein levels. The LIF receptor gp190 subunit (LIFR) couples with the IL-6 receptor subunit and binds LIF and other neurotropic cytokines to relay intracellular neurosurvival signaling. The above three- dose treatment regimen significantly increased expression of LIFR in the ipsilateral hemisphere of the brain at 72 h after stroke compared to sham surgery and PBS treatment. LIFR mRNA levels were significantly elevated in cultured neurons that were treated with LIF prior to 24 h in vitro ischemia compared to neurons that were treated with PBS. LIFR is localized to neuronal nuclei in the uninjured brain. During brain injury, LIF receptor translocates to the cell membrane and this translocation is enhanced by LIF treatment. However, LIF treatment of aged female and male rats (1.5 yo) does not increase LIFR expression and is not as neuroprotective after MCAO using this 3 dose regimen. Endothelial LIFR transports LIF transporter across the blood brain barrier. The aged brain would have reduced transport of LIF to the infarct and thus, decreased neuroprotection. Since most stroke studies utilize young rats and the human stroke population is aged, this finding could explain at least partially why rodent studies do not translate to human ones. We are further examining LIFR expression at the blood-brain barrier to determine if this transporter is the key to a reduced response to LIF treatment in elderly rats.
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| Biography:
Keith R. Pennypacker, PhD, Professor, Associate Director of the Center for Advanced Translational Stroke Science, University of Kentucky, Department of Neurology, College of Medicine. Dr. Pennypacker completed his PhD in Pharmacology at Pennsylvania State University, followed by postdoctoral training at the National Institute of Environmental Health Sciences. He joined the Department of Pharmacology at the University of South Florida in 1995. After 21 years, he moved to the University of Kentucky to take the position as Associate Director of the Center for Advanced Translational Stroke Science. Dr. Pennypacker’s general area of research expertise has been in area of neurodegeneration after injury but now is investigating novel therapeutic strategies for stroke treatment. These therapies target signal transduction pathways that enhance the survival of neural cells and reduce inflammation. His lab has reported that the post-stroke inflammation originates in the spleen in ischemic and traumatic brain injury. His research efforts have been supported with grants from the American Heart Association and the NIH.
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