THERAPEUTIC EFFECTS OF AN INSULIN-LIKE GROWTH FACTOR I SENSITIZER IN TRAUMATIC BRAIN INJURY

Abstract

Traumatic brain injury (TBI) is a condition of high incidence worldwide, but remains mostly undertreated. Previous observations in preclinical studies pointed to a beneficial effect of insulin-like growth factor 1 (IGF-1) in TBI. As brain injury is associated to loss of IGF-1 sensitivity, we tested the therapeutic potential of AIK3a305 (AIK3), a novel IGF-1 sensitizer. Twenty-four hours after mild TBI induced by controlled impact, mice received daily intraperitoneal injections of AIK3 during 4 weeks. We found that TBI-associated sensorimotor disturbances measured with the adhesive-removal test were reverted by AIK3 treatment. In addition, neurological and cognitive disturbances measured by the neurological severity score and Y maze respectively, were also ameliorated by treatment with the IGF-1 sensitizer, whereas increased anxiety after mild TBI was also normalized by AIK3. Circulating levels of IGF-1 were increased after AIK3 treatment in TBI mice, while serum IL-6 levels, a biomarker of inflammation associated to TBI were similar to control mice treated with AIK3. Transcriptomic analysis determined that treatment with AIK3 widely affected gene expression in TBI brains, showing a general reduction in both up- and down-regulated genes. Collectively, these data support the use of IGF-1 sensitizers such as AIK3 for treatment of TBI.