The effect of gene therapy with the APOE3 Gene on structural and functional manifestations of secondary hippocampal damages in experimental traumatic brain injury

Abstract

to study the efficiency of gene therapy following traumatic brain injury (TBI) by evaluating the influences of liposomal transfection of the brain tissue by APOE3-containing plasmid vector on the structural and functional manifestations of development of secondary brain injuries after acute experimental TBI in the rats of different age. Severe diffuse TBI in rats was inflicted under overall anesthesia by free load weighing 450 g, falling from a 1.5 m elevation. The mixture of DOTAP liposome and 25 μg of plasmid vector pCMV·SPORT6 with cDNA of APOE3 gene was infused intraventricularly using ALZET osmotic pumps. Combined morphological, electron microscopic, immunohistochemical and morphometric studies of СА1 hippocampal region were conducted in rats at days 5 and 10 following TBI and gene therapy after investigation of motor functions (using composite neurological motor score) and cognitive functions in Morris water maze. Significant changes in the morphofunctional state of hippocampus, as well as in the neurological and cognitive functions were shown on the model of severe TBI in the adult and old Wistar rats. Gene therapy, specifically cationic-liposome mediated APOE3 gene transfer to the CNS cells by plasmid vector, decreased a TBI-induced death of neurons and improved qualitative composition of neuronal population, normalized neuron-glial relations, decreased gliosis and microglial activation, axonal damage, myelin destruction and lipofuscin accumulation, all these having age-related peculiarities. After gene therapy observed in the animal brain was a lower intensity of the processes of apoptosis and a decrease of its rate in old animals. The above changes were accompanied with a more fast and expressed regress of neurological and cognitive disturbances typical for TBI. Administration of plasmid vector after TBI resulted in an increase of survival rate of old animals vs. old animals which got no gene therapy. APOE3 gene therapy has therapeutic potential in the treatment of severe TBI.