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

• Published in: Neurochemical research 2017-12, Vol.42 (12), p.3401-3413
• Main Authors: Sommer, Jens Bak, Bach, Anders, Malá, Hana, Gynther, Mikko, Bjerre, Ann-Sofie, Gram, Marie Gajhede, Marschner, Linda, Strømgaard, Kristian, Mogensen, Jesper, Pickering, Darryl S.
• Format: Article
• Language: English
• Subjects: Animal memory; Animals; Apoptosis; Biochemistry; Biocompatibility; Biomedical and Life Sciences; Biomedicine; Brain; Brain Injuries, Traumatic - drug therapy; Cell Biology; Cell death; Cell Death - drug effects; Central nervous system; Cortex; Disease Models, Animal; Disks Large Homolog 4 Protein - antagonists & inhibitors; Excitotoxicity; Head injuries; In vivo methods and tests; Inhibition; Inhibitors; Maze learning; Maze Learning - drug effects; Memory - drug effects; Mice; N-Methyl-D-aspartic acid; Neurochemistry; Neurology; Neurons - drug effects; Neurosciences; Neurotoxicity; Oligopeptides - pharmacology; Original Paper; Pharmacology; Postsynaptic density proteins; Rats; Rodents; Spatial discrimination learning; Spatial memory; Stroke; Studies; Toxicity; Traumatic brain injury
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-017-2381-y

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.