Pharmacology and Therapeutics - Research Publications

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Author: Daglas, Maria × End date: 2019 ×

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    Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury
    Karve, IP ; Zhang, M ; Habgood, M ; Frugier, T ; Brody, KM ; Sashindranath, M ; Ek, CJ ; Chappaz, S ; Kile, BT ; Wright, D ; Wang, H ; Johnston, L ; Daglas, M ; Ates, RC ; Medcalf, RL ; Taylor, JM ; Crack, PJ (SOC NEUROSCIENCE, 2016)
    Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.
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    Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes
    Crack, PJ ; Zhang, M ; Morganti-Kossmann, MC ; Morris, AJ ; Wojciak, JM ; Fleming, JK ; Karve, I ; Wright, D ; Sashindranath, M ; Goldshmit, Y ; Conquest, A ; Daglas, M ; Johnston, LA ; Medcalf, RL ; Sabbadini, RA ; Pebay, A (BIOMED CENTRAL LTD, 2014-02-27)
    BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. FINDINGS: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. CONCLUSIONS: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.