Effects of Dimeric PSD-95 Inhibition on Excitotoxic Cell Death and Outcome After Controlled Cortical Impact in Rats.

Autor: Sommer JB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100, Copenhagen, Denmark. jens.sommer@sund.ku.dk.; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark. jens.sommer@sund.ku.dk., Bach A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100, Copenhagen, Denmark., Malá H; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark., Gynther M; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Bjerre AS; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark., Gram MG; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark., Marschner L; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark., Strømgaard K; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100, Copenhagen, Denmark., Mogensen J; The Unit for Cognitive Neuroscience (UCN), Department of Psychology, Faculty of Social Sciences, University of Copenhagen, Copenhagen, Denmark., Pickering DS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Neurochemical research [Neurochem Res] 2017 Dec; Vol. 42 (12), pp. 3401-3413. Date of Electronic Publication: 2017 Aug 21.
DOI: 10.1007/s11064-017-2381-y
Abstrakt: Therapeutic effects of PSD-95 inhibition have been demonstrated in numerous studies of stroke; however only few studies have assessed the effects of PSD-95 inhibitors in traumatic brain injury (TBI). As the pathophysiology of TBI partially overlaps with that of stroke, PSD-95 inhibition may also be an effective therapeutic strategy in TBI. The objectives of the present study were to assess the effects of a dimeric inhibitor of PSD-95, UCCB01-144, on excitotoxic cell death in vitro and outcome after experimental TBI in rats in vivo. In addition, the pharmacokinetic parameters of UCCB01-144 were investigated in order to assess uptake of the drug into the central nervous system of rats. After a controlled cortical impact rats were randomized to receive a single injection of either saline or two different doses of UCCB01-144 (10 or 20 mg/kg IV) immediately after injury. Spatial learning and memory were assessed in a water maze at 2 weeks post-trauma, and at 4 weeks lesion volumes were estimated. Overall, UCCB01-144 did not protect against NMDA-toxicity in neuronal cultures or experimental TBI in rats. Important factors that should be investigated further in future studies assessing the effects of PSD-95 inhibitors in TBI are discussed.
Databáze: MEDLINE
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