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J Neurotrauma. 2018 Jul 1;35(13):1467-1480. doi: 10.1089/neu.2017.5374. Epub 2018 Apr 17.

Central Infusion of Insulin-Like Growth Factor-1 Increases Hippocampal Neurogenesis and Improves Neurobehavioral Function after Traumatic Brain Injury.

Author information

1
Spinal Cord and Brain Injury Research Center, University of Kentucky , Lexington, Kentucky.

Abstract

Traumatic brain injury (TBI) produces neuronal dysfunction and cellular loss that can culminate in lasting impairments in cognitive and motor abilities. Therapeutic agents that promote repair and replenish neurons post-TBI hold promise in improving recovery of function. Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor capable of mediating neuroprotective and neuroplasticity mechanisms. Targeted overexpression of IGF-1 enhances the generation of hippocampal newborn neurons in brain-injured mice; however, the translational neurogenic potential of exogenously administered IGF-1 post-TBI remains unknown. In a mouse model of controlled cortical impact, continuous intracerebroventricular infusion of recombinant human IGF-1 (hIGF) for 7 days, beginning 15 min post-injury, resulted in a dose-dependent increase in the number of immature neurons in the hippocampus. Infusion of 10 μg/day of IGF-1 produced detectable levels of hIGF-1 in the cortex and hippocampus and a concomitant increase in protein kinase B activation in the hippocampus. Both motor function and cognition were improved over 7 days post-injury in IGF-1-treated cohorts. Vehicle-treated brain-injured mice showed reduced hippocampal immature neuron density relative to sham controls at 7 days post-injury. In contrast, the density of hippocampal immature neurons in brain-injured mice receiving acute onset IGF-1 infusion was significantly higher than in injured mice receiving vehicle and equivalent to that in sham-injured control mice. Importantly, the neurogenic effect of IGF-1 was maintained with as much as a 6-h delay in the initiation of infusion. These data suggest that central infusion of IGF-1 enhances the generation of immature neurons in the hippocampus, with a therapeutic window of at least 6 h post-injury, and promotes neurobehavioral recovery post-TBI.

KEYWORDS:

IGF-1; TBI; cognition; hippocampus; neurogenesis

PMID:
29455576
PMCID:
PMC5998830
DOI:
10.1089/neu.2017.5374

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