TY - JOUR
T1 - Effects of dimeric PSD-95 inhibition on excitotoxic cell death and outcome after controlled cortical impact in rats
T2 - PSD-95 inhibition in experimental TBI
AU - Sommer, Jens Bak
AU - Bach, Anders
AU - Rytter, Hana Malá
AU - Gynther, Mikko
AU - Bjerre, Ann-Sofie
AU - Gram, Marie Gajhede
AU - Marschner, Linda
AU - Strømgaard, Kristian
AU - Mogensen, Jesper
AU - Pickering, Darryl S
PY - 2017
Y1 - 2017
N2 - 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 two weeks post-trauma, and at four 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.
AB - 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 two weeks post-trauma, and at four 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.
U2 - 10.1007/s11064-017-2381-y
DO - 10.1007/s11064-017-2381-y
M3 - Journal article
C2 - 28828633
SN - 0364-3190
VL - 42
SP - 3401
EP - 3413
JO - Neurochemical Research
JF - Neurochemical Research
IS - 12
ER -