A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury

The tetra (ethylene glycol) derivative of benzothiazole aniline (SPG101) has been shown to improve dendritic spine density and cognitive memory in the triple transgenic mouse model of Alzheimer disease (AD) when administered intraperitoneally. The present study was designed to investigate the therapeutic effects of SPG101 on dendritic spine density and morphology and sensorimotor and cognitive functional recovery in a rat model of traumatic brain injury (TBI) induced by controlled cortical impact (CCI). Young adult male Wistar rats with CCI were randomly divided into the following two groups (n=7/group): (1) Vehicle, and (2) SPG101. SPG101 (30mg/kg) dissolved in vehicle (1% dimethyl sulfoxide in phosphate buffered saline) or Vehicle were intraperitoneally administered starting at 1h post-injury and once daily for the next 34 days. Sensorimotor deficits were assessed using a modified neurological severity score and adhesive removal and foot fault tests. Cognitive function was measured by Morris water maze, novel object recognition (NOR), and three-chamber social recognition tests. The animals were sacrificed 35 days after injury, and their brains were processed for measurement of dendritic spine density and morphology using ballistic dye labeling. Compared with the vehicle treatment, SPG101 treatment initiated 1h post-injury significantly improved sensorimotor functional recovery (days 7-35, p<0.0001), spatial learning (days 32-35, p<0.0001), NOR (days 14 and 35, p<0.0001), social recognition (days 14 and 35, p<0.0001). Further, treatment significantly increased dendritic spine density in the injured cortex (p<0.05), decreased heterogeneous distribution of spine lengths in the injured cortex and hippocampus (p<0.0001), modifications that are associated with the promotion of spine maturation in these brain regions. In summary, treatment with SPG101 initiated 1h post-injury and continued for an additional 34 days improves both sensorimotor and cognitive functional recovery, indicating that SPG101 acts as a spinogenic agent and may have potential as a novel treatment of TBI.