Browsing by Author "Fok, S"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Positron emission tomography and functional characterization of a complete PBR/TSPO knockout
    (Springer Nature, 2014-11-19) Banati, RB; Middleton, RJ; Chan, RHY; Hatty, CR; Wai-Ying Kam, W; Quin, C; Graeber, MB; Parmar, A; Zahra, D; Callaghan, PD; Fok, S; Howell, NR; Grégoire, MC; Szabo, A; Pham, TQ; Davis, E; Liu, GJ
    The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer’s disease to anxiety. Here we show that global C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from GuwiyangWurraTSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of GuwiyangWurraTSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs. Copyright © 2014, Springer Nature
  • No Thumbnail Available
    Item
    Up-regulation of matrix metallopeptidase 12 in motor neurons undergoing synaptic stripping
    (Elsevier B.V., 2014-08-22) Sajjan, S; Holsinger, RMD; Fok, S; Ebrahimkhani, S; Rollo, JL; Banati, RB; Graeber, MB
    Axotomy of the rodent facial nerve represents a well-established model of synaptic plasticity. Post-traumatic “synaptic stripping” was originally discovered in this system. We report upregulation of matrix metalloproteinase MMP12 in regenerating motor neurons of the mouse and rat facial nucleus. Matrix metalloproteinases (matrix metallopeptidases, MMPs) are zinc-binding proteases capable of degrading components of the extracellular matrix and of regulating extracellular signaling networks including within synapses. MMP12 protein expression in facial motor neurons was enhanced following axotomy and peaked at day 3 after the operation. The peak of neuronal MMP12 expression preceded the peak of experimentally induced synaptic plasticity. At the same time, MMP12 redistributed intracellularly and became predominantly localized beneath the neuronal somatic cytoplasmic membrane. Both findings point to a role of MMP12 in the neuronal initiation of the synaptic stripping process. MMP12 is the first candidate molecule for such a trigger function and has potential as a therapeutic target. Moreover, since statins have been shown to increase the expression of MMP12, interference with synaptic stability may represent one mechanism by which these widely used drugs exert their side effects on higher CNS functions. © 2014 by Elsevier Ltd.