Medicine and Health Sciences Commons^™

Inhibition Of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade And Promotes Recovery After Spinal Cord Injury, Chen Guang Yu, Vimala Bondada, Hina Iqbal, Kate L. Moore, John C. Gensel, Subbarao Bondada, James W. Geddes

Physiology Faculty Publications

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib …

Oligodendrocyte Responses After Spinal Cord Injury., George Zach Wei

Electronic Theses and Dissertations

Recent studies demonstrate that neuroprotection strategies targeting the proteostasis network and components of its effector signaling pathways improve cell survival and motor recovery outcomes in several models of neuronal injury and degeneration. However, the individual contributions of these signaling pathways to the pathogenesis of spinal cord injury (SCI), white matter damage, and motor recovery have not yet been determined. Here, I explored the role of the HIF prolyl hydroxylase domain proteins (PHD/EGLN), effectors that can modulate stress responses activated by the proteostasis network, on motor function recovery after SCI. Furthermore, I identified previously unknown candidate mechanisms in an unbiased manner …

Apolipoprotein E Genotype-Dependent Nutrigenetic Effects To Prebiotic Inulin For Modulating Systemic Metabolism And Neuroprotection In Mice Via Gut-Brain Axis, Lucille M. Yanckello, Jared D. Hoffman, Ya-Hsuan Chang, Penghui Lin, Geetika Nehra, George Chlipala, Scott D. Mcculloch, Tyler C. Hammond, Andrew T. Yackzan, Andrew N. Lane, Stefan J. Green, Anika M. S. Hartz, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE: The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with human APOE ϵ3 and ϵ4 alleles.

METHOD: We performed experiments with young mice expressing the human APOE3 (E3FAD mice and APOE4 gene (E4FAD mice). We fed mice with either inulin or control diet for 16 weeks starting from 3 months of age. We determined gut microbiome …

Genetic Approach To Elucidate The Role Of Cyclophilin D In Traumatic Brain Injury Pathology, Ryan D. Readnower, W. Brad Hubbard, Olivia J. Kalimon, James W. Geddes, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the …

Mitochondria Exert Age-Divergent Effects On Recovery From Spinal Cord Injury, Andrew N. Stewart, Katelyn E. Mcfarlane, Hemendra J. Vekaria, William M. Bailey, Stacey A. Slone, Lauren A. Tranthem, Bei Zhang, Samir P. Patel, Patrick G. Sullivan, John C. Gensel

Physiology Faculty Publications

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue …

Therapeutic Potential Of Mitophagy-Inducing Microflora Metabolite, Urolithin A For Alzheimer’S Disease, Dona Pamoda W. Jayatunga, Eugene Hone, Harjot Khaira, Taciana Lunelli, Harjinder Singh, Gilles J. Guillemin, Binosha Fernando, Manohar L. Garg, Giuseppe Verdile, Ralph N. Martins

Research outputs 2014 to 2021

Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neuro-degenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bi-oactive food components, known as nutraceuticals, may serve as such agents to combat AD. Uro-lithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, …